PDZ domain of membrane palmitoylated protein 6 (MPP6), MPP2, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of MPP6, MPP2, and related domains. MPP6 (also known as MAGUK p55 subfamily member, Protein associated with Lin-7, 2 (PALS2), Veli-associated MAGUK 1, and VAM-1) is a membrane-associated guanylate kinase (MAGUK)-like protein. MPP6 is a regulator of Lin-7 expression and localization. MPP6 is also known to bind cell-adhesion protein, nectin-like molecule-2 (Necl-2), and localize to the basolateral plasma membrane in mammalian epithelial cells. MPP2 (also known as MAGUK p55 subfamily member 2) is a postsynaptic protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density. Other members of this family include the Drosophila Vari protein, an essential basolateral septate junction protein which interacts with the cell-adhesion protein neurexin IV. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This MPP6-MPP2-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 442628659   7 KMVGLRRDPSKPLGLTVELDEfKQLVVARILAGGVIDKQSMLHVGDVILEVNGTPVRTPDELQVEVSRAKENLTLKIGP 85
Cdd:cd10832    1 RMVGIRKNPGEPLGVTVRLEE-GELVIARILHGGMIDRQGLLHVGDIIKEVNGVPVGSPEQLQEMLKNASGSVTLKILP 78

Guanylate kinase homologues; Active enzymes catalyze ATP-dependent phosphorylation of GMP to GDP. Structure resembles that of adenylate kinase. So-called membrane-associated guanylate kinase homologues (MAGUKs) do not possess guanylate kinase activities; instead at least some possess protein-binding functions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659   251 SGVGRRTLKNRLINSDVDKFGAVIPHTSRPKRALEENGSSYWFMDREEMEEAVRNNEFLEYGEHNGNLYGTHLQSIKDVI 330
Cdd:smart00072   1 SGVGKGTLLAELIQEIPDAFERVVSHTTRPPRPGEVNGVDYHFVSKEEFEDDIKSGLFLEWGEYEGNYYGTSKETIRQVA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659   331 NSGRMCILDCAPNALKILHNSQeLMPFVIFVAAPGMEQLKTiyadrraTGSNRNLSFDRQssirfSSRRARTLESLASLY 410
Cdd:smart00072  81 EKGKHCLLDIDPQGVKQLRKAQ-LYPIVIFIAPPSSEELER-------RLRQRGTETSER-----IQKRLAAAQKEAQEY 147

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*
gi 442628659   411 EdddlvatveessfvqrkyekYFDMVIVNEDFDETFRQVVETLDQ 455
Cdd:smart00072 148 H--------------------LFDYVIVNDDLEDAYEELKEILEA 172

Src Homology 3 domain of Membrane Protein, Palmitoylated (or MAGUK p55 subfamily member) proteins; The MPP/p55 subfamily of MAGUK (membrane-associated guanylate kinase) proteins includes at least eight vertebrate members (MPP1-7 and CASK), four Drosophila proteins (Stardust, Varicose, CASK and Skiff), and other similar proteins; they all contain one each of the core of three domains characteristic of MAGUK proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, most members except for MPP1 contain N-terminal L27 domains and some also contain a Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. CASK has an additional calmodulin-dependent kinase (CaMK)-like domain at the N-terminus. Members of this subfamily are scaffolding proteins that play important roles in regulating and establishing cell polarity, cell adhesion, and synaptic targeting and transmission, among others. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 442628659 120 YMRALFTYNPSEDSLLPCRDIGLPFKSGDILQIINVKDPNWWQAKNITAESDKIGLIPSQE 180
Cdd:cd11862    1 FVRALFDYDPEEDPLIPCKEAGLSFKKGDILQIVNQDDPNWWQARKVGDPNGRAGLIPSQD 61

Guanylate kinase [Nucleotide transport and metabolism];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659 245 LVLIGVSGVGRRTLKNRLINSDVDkFGAVIPHTSRPKRALEENGSSYWFMDREEMEEAVRNNEFLEYGEHNGNLYGTHLQ 324
Cdd:COG0194    5 IVLSGPSGAGKTTLVKALLERDPD-LRFSVSATTRPPRPGEVDGVDYHFVSREEFERMIENGEFLEWAEVHGNYYGTPKA 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659 325 SIKDVINSGRMCILDCAPN-ALKIlhnsQELMPFV--IFVAAPGMEQLKtiyadRRATGsnRNLsfDRQSSIRfssRRAR 401
Cdd:COG0194   84 EVEEALAAGKDVLLEIDVQgARQV----KKKFPDAvsIFILPPSLEELE-----RRLRG--RGT--DSEEVIE---RRLA 147

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|..
gi 442628659 402 TleslaslyedddlvATVEESsfvqrkYEKYFDMVIVNEDFDETFRQVVETL 453
Cdd:COG0194  148 K--------------AREELA------HADEFDYVVVNDDLDRAVEELKAII 179

guanylate kinase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659 243 KTLVLIGVSGVGRRTLKNRLINSDVDKFGAVIPHTSRPKRALEENGSSYWFMDREEMEEAVRNNEFLEYGEHNGNLYGTH 322
Cdd:PLN02772 136 KPIVISGPSGVGKGTLISMLMKEFPSMFGFSVSHTTRAPREMEKDGVHYHFTERSVMEKEIKDGKFLEFASVHGNLYGTS 215

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659 323 LQSIKDVINSGRMCILDCAPNALKILHNSQeLMPFVIFVAAPGMEQLKTiyadrratgsnrnlsfdrqssiRFSSRRART 402
Cdd:PLN02772 216 IEAVEVVTDSGKRCILDIDVQGARSVRASS-LEAIFIFICPPSMEELEK----------------------RLRARGTET 272

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|..
gi 442628659 403 LESLASLYEDDDLVATVEESSFVqrkyekyFDMVIVNEDFDETFRQVVETLD 454
Cdd:PLN02772 273 EEQIQKRLRNAEAELEQGKSSGI-------FDHILYNDNLEECYKNLKKLLG 317

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 442628659  122 RALFTYNPSEDSllpcrdiGLPFKSGDILQIINVKDPNWWQAKNITaesDKIGLIPS 178
Cdd:pfam00018   1 VALYDYTAQEPD-------ELSFKKGDIIIVLEKSEDGWWKGRNKG---GKEGLIPS 47

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659     6 IKMVGLRRDPsKPLGLTV--ELDEFKQLVVARILAGGVIDKQSmLHVGDVILEVNGTPVR--TPDELQVEVSRAKENLTL 81
Cdd:smart00228   2 PRLVELEKGG-GGLGFSLvgGKDEGGGVVVSSVVPGSPAAKAG-LRVGDVILEVNGTSVEglTHLEAVDLLKKAGGKVTL 79

                   ..
gi 442628659    82 KI 83
Cdd:smart00228  80 TV 81

periplasmic serine protease, Do/DeqQ family; This family consists of a set proteins various designated DegP, heat shock protein HtrA, and protease DO. The ortholog in Pseudomonas aeruginosa is designated MucD and is found in an operon that controls mucoid phenotype. This family also includes the DegQ (HhoA) paralog in E. coli which can rescue a DegP mutant, but not the smaller DegS paralog, which cannot. Members of this family are located in the periplasm and have separable functions as both protease and chaperone. Members have a trypsin domain and two copies of a PDZ domain. This protein protects bacteria from thermal and other stresses and may be important for the survival of bacterial pathogens.// The chaperone function is dominant at low temperatures, whereas the proteolytic activity is turned on at elevated temperatures. [Protein fate, Protein folding and stabilization, Protein fate, Degradation of proteins, peptides, and glycopeptides]

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 442628659   33 VARILAGGVIDKqSMLHVGDVILEVNGTPVRTPDELQVEVSRAK--ENLTLKI 83
Cdd:TIGR02037 261 VAQVLPGSPAEK-AGLKAGDVITSVNGKPISSFADLRRAIGTLKpgKKVTLGI 312

Guanylate kinase homologues; Active enzymes catalyze ATP-dependent phosphorylation of GMP to GDP. Structure resembles that of adenylate kinase. So-called membrane-associated guanylate kinase homologues (MAGUKs) do not possess guanylate kinase activities; instead at least some possess protein-binding functions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659   251 SGVGRRTLKNRLINSDVDKFGAVIPHTSRPKRALEENGSSYWFMDREEMEEAVRNNEFLEYGEHNGNLYGTHLQSIKDVI 330
Cdd:smart00072   1 SGVGKGTLLAELIQEIPDAFERVVSHTTRPPRPGEVNGVDYHFVSKEEFEDDIKSGLFLEWGEYEGNYYGTSKETIRQVA 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659   331 NSGRMCILDCAPNALKILHNSQeLMPFVIFVAAPGMEQLKTiyadrraTGSNRNLSFDRQssirfSSRRARTLESLASLY 410
Cdd:smart00072  81 EKGKHCLLDIDPQGVKQLRKAQ-LYPIVIFIAPPSSEELER-------RLRQRGTETSER-----IQKRLAAAQKEAQEY 147

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*
gi 442628659   411 EdddlvatveessfvqrkyekYFDMVIVNEDFDETFRQVVETLDQ 455
Cdd:smart00072 148 H--------------------LFDYVIVNDDLEDAYEELKEILEA 172

Src Homology 3 domain of Membrane Protein, Palmitoylated (or MAGUK p55 subfamily member) proteins; The MPP/p55 subfamily of MAGUK (membrane-associated guanylate kinase) proteins includes at least eight vertebrate members (MPP1-7 and CASK), four Drosophila proteins (Stardust, Varicose, CASK and Skiff), and other similar proteins; they all contain one each of the core of three domains characteristic of MAGUK proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, most members except for MPP1 contain N-terminal L27 domains and some also contain a Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. CASK has an additional calmodulin-dependent kinase (CaMK)-like domain at the N-terminus. Members of this subfamily are scaffolding proteins that play important roles in regulating and establishing cell polarity, cell adhesion, and synaptic targeting and transmission, among others. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 442628659 120 YMRALFTYNPSEDSLLPCRDIGLPFKSGDILQIINVKDPNWWQAKNITAESDKIGLIPSQE 180
Cdd:cd11862    1 FVRALFDYDPEEDPLIPCKEAGLSFKKGDILQIVNQDDPNWWQARKVGDPNGRAGLIPSQD 61

Guanylate kinase [Nucleotide transport and metabolism];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659 245 LVLIGVSGVGRRTLKNRLINSDVDkFGAVIPHTSRPKRALEENGSSYWFMDREEMEEAVRNNEFLEYGEHNGNLYGTHLQ 324
Cdd:COG0194    5 IVLSGPSGAGKTTLVKALLERDPD-LRFSVSATTRPPRPGEVDGVDYHFVSREEFERMIENGEFLEWAEVHGNYYGTPKA 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659 325 SIKDVINSGRMCILDCAPN-ALKIlhnsQELMPFV--IFVAAPGMEQLKtiyadRRATGsnRNLsfDRQSSIRfssRRAR 401
Cdd:COG0194   84 EVEEALAAGKDVLLEIDVQgARQV----KKKFPDAvsIFILPPSLEELE-----RRLRG--RGT--DSEEVIE---RRLA 147

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|..
gi 442628659 402 TleslaslyedddlvATVEESsfvqrkYEKYFDMVIVNEDFDETFRQVVETL 453
Cdd:COG0194  148 K--------------AREELA------HADEFDYVVVNDDLDRAVEELKAII 179

Src Homology 3 domain of Membrane Protein, Palmitoylated 1 (or MAGUK p55 subfamily member 1)-like proteins; This subfamily includes MPP1, CASK (Calcium/calmodulin-dependent Serine protein Kinase), Caenorhabditis elegans lin-2, and similar proteins. MPP1 and CASK are scaffolding proteins from the MAGUK (membrane-associated guanylate kinase) protein family, which is characterized by the presence of a core of three domains: PDZ, SH3, and guanylate kinase (GuK). In addition, they also have the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. CASK and lin-2 also contain an N-terminal calmodulin-dependent kinase (CaMK)-like domain and two L27 domains. MPP1 is ubiquitously-expressed and plays roles in regulating neutrophil polarity, cell shape, hair cell development, and neural development and patterning of the retina. CASK is highly expressed in the mammalian nervous system and plays roles in synaptic protein targeting, neural development, and gene expression regulation. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 442628659 120 YMRALFTYNPSEDSLLPCRDIGLPFKSGDILQIINVKDPNWWQAKNITAESDKIGLIPSQEL 181
Cdd:cd12035    1 YVRAQFDYDPSKDDLIPCQQAGIAFKTGDILQIISKDDHNWWQARKPGASKEPAGLIPSPEL 62

guanylate kinase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659 245 LVLIGVSGVGRRTLKNRLINSDvDKFGAVIPHTSRPKRALEENGSSYWFMDREEMEEAVRNNEFLEYGEHNGNLYGTHLQ 324
Cdd:PRK00300   8 IVLSGPSGAGKSTLVKALLERD-PNLQLSVSATTRAPRPGEVDGVDYFFVSKEEFEEMIENGEFLEWAEVFGNYYGTPRS 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659 325 SIKDVINSGRMCIL--DCApNALKIlhnsQELMPFV--IFVAAPGMEQLKtiyaDR---RATgsnrnlsfDRQSSIRfss 397
Cdd:PRK00300  87 PVEEALAAGKDVLLeiDWQ-GARQV----KKKMPDAvsIFILPPSLEELE----RRlrgRGT--------DSEEVIA--- 146

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|...
gi 442628659 398 RRartleslaslyedddLVATVEESSFVQRkyekyFDMVIVNEDFDETFRQVV 450
Cdd:PRK00300 147 RR---------------LAKAREEIAHASE-----YDYVIVNDDLDTALEELK 179

Src Homology 3 domain of Membrane Protein, Palmitoylated 3 (or MAGUK p55 subfamily member 3); MPP3 is a scaffolding protein that colocalizes with MPP5 and CRB1 at the subdpical region adjacent to adherens junctions and may function in photoreceptor polarity. It interacts with some nectins and regulates their trafficking and processing. Nectins are cell-cell adhesion proteins involved in the establishment apical-basal polarity at cell adhesion sites. It is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 442628659 120 YMRALFTYNPSEDSLLPCRDIGLPFKSGDILQIINVKDPNWWQAKNITAESDKIGLIPSQEL 181
Cdd:cd12039    1 FMRALFDYNPYEDRAIPCQEAGLPFKRRDILEVVSQDDPTWWQAKRVGDTNLRAGLIPSKQF 62

Src Homology 3 domain of Membrane Protein, Palmitoylated 5 (or MAGUK p55 subfamily member 5); MPP5, also called PALS1 (Protein associated with Lin7) or Nagie oko protein in zebrafish or Stardust in Drosophila, is a scaffolding protein which associates with Crumbs homolog 1 (CRB1), CRB2, or CRB3 through its PDZ domain and with PALS1-associated tight junction protein (PATJ) or multi-PDZ domain protein 1 (MUPP1) through its L27 domain. The resulting tri-protein complexes are core proteins of the Crumb complex, which localizes at tight junctions or subapical regions, and is involved in the maintenance of apical-basal polarity in epithelial cells and the morphogenesis and function of photoreceptor cells. MPP5 is critical for the proper stratification of the retina and is also expressed in T lymphocytes where it is important for TCR-mediated activation of NFkB. Drosophila Stardust exists in several isoforms, some of which show opposing functions in photoreceptor cells, which suggests that the relative ratio of different Crumbs complexes regulates photoreceptor homeostasis. MPP5 contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 442628659 120 YMRALFTYNPSEDSLLPCRDIGLPFKSGDILQIINVKDPNWWQAKNITAESDK--IGLIPSQE 180
Cdd:cd12036    1 HVRAHFDYDPEDDPYIPCRELGLSFQKGDILHVISQEDPNWWQAYREGEEDNQslAGLIPSKS 63

Src Homology 3 domain of Membrane Protein, Palmitoylated 2 (or MAGUK p55 subfamily member 2); MPP2 is a scaffolding protein that interacts with the non-receptor tyrosine kinase c-Src in epithelial cells to negatively regulate its activity and morphological function. It is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659 120 YMRALFTYNPSEDSLLPCRDIGLPFKSGDILQIINVKDPNWWQAKNItaESDKIGLIPSQ 179
Cdd:cd12037    1 FVKCHFDYDPSSDSLIPCKEAGLKFRAGDLLQIVNQEDPNWWQACHV--EGGSAGLIPSQ 58

Src Homology 3 domain of Disks large homolog proteins; The DLG-like proteins are scaffolding proteins that cluster at synapses and are also called PSD (postsynaptic density)-95 proteins or SAPs (synapse-associated proteins). They play important roles in synaptic development and plasticity, cell polarity, migration and proliferation. They are members of the MAGUK (membrane-associated guanylate kinase) protein family, which is characterized by the presence of a core of three domains: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. DLG-like proteins contain three PDZ domains and varying N-terminal regions. All DLG proteins exist as alternatively-spliced isoforms. Vertebrates contain four DLG proteins from different genes, called DLG1-4. DLG4 and DLG2 are found predominantly at postsynaptic sites and they mediate surface ion channel and receptor clustering. DLG3 is found axons and some presynaptic terminals. DLG1 interacts with AMPA-type glutamate receptors and is critical in their maturation and delivery to synapses. The SH3 domain of DLG4 binds and clusters the kainate subgroup of glutamate receptors via two proline-rich sequences in their C-terminal tail. It also binds AKAP79/150 (A-kinase anchoring protein). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 442628659 120 YMRALFTYNPSEDSLLPCRdiGLPFKSGDILQIINVKDPNWWQAKNITA--ESDKIGLIPS 178
Cdd:cd11861    1 YVRALFDYDPSRDSGLPSQ--GLSFKFGDILHVTNASDDEWWQARRVTPngEEEEVGVIPS 59

Src Homology 3 domain of Membrane Protein, Palmitoylated 6 (or MAGUK p55 subfamily member 6); MPP6, also called Veli-associated MAGUK 1 (VAM-1) or PALS2, is a scaffolding protein that binds to Veli-1, a homolog of Caenorhabditis Lin-7. It is one of seven vertebrate homologs of the Drosophila Stardust protein, which is required in establishing cell polarity, and it contains two L27 domains followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 442628659 120 YMRALFTYNPSEDSLLPCRDIGLPFKSGDILQIINVKDPNWWQAKNITaESDKIGLIPSQEL 181
Cdd:cd12038    1 FVKCHFDYNPYNDNLIPCKEAGLKFSKGEILQIVNREDPNWWQASHVK-EGGSAGLIPSQFL 61

PDZ domain of membrane palmitoylated protein1 (MPP1), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of MPP1, and related domains. MPP1 (also known as MAGUK p55 subfamily member 1, erythrocyte membrane protein p55, EMP55) is a membrane-associated guanylate kinase (MAGUK)-like protein which forms a complex with protein 4.1 and glycophorin C (GPC) at the cytoplasmic face of the plasma membrane; this complex is essential for cytoskeleton-membrane linkage in erythrocytes and many non-erythroid cells, and participates in the determination of membrane stability and cell shape. MPP1, by interacting with various scaffold proteins and cytoskeletal proteins in the postsynaptic density, also plays an important role in organizing synaptic and non-synaptic structures. MPP1 is also a component of the Crumbs protein complex in the mammalian retina and may link the Usher protein network and the Crumbs protein complex. The MPP1 PDZ domain binding partners include GPC, ABCC4, and CADM1/Necl-2/SynCAM1. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This MPP1-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659   7 KMVGLRRDPSKPLGLTVELDEFKQLVVARILAGGVIDKQSMLHVGDVILEVNGTPVR--TPDELQVEVSRAKENLTLKIG 84
Cdd:cd10830    1 RLVQFEKNTEEPMGITLKLNEKQSCIVARILHGGMIHRQGSLHVGDEILEINGKSVTnhSVDQLQKMLKETKGMVSLKVI 80

                 .
gi 442628659  85 P 85
Cdd:cd10830   81 P 81

Src Homology 3 domain of Disks Large homolog 1; DLG1, also called synapse-associated protein 97 (SAP97), is a scaffolding protein that clusters at synapses and plays an important role in synaptic development and plasticity. DLG1 plays roles in regulating cell polarity, proliferation, migration, and cycle progression. It interacts with AMPA-type glutamate receptors and is critical in their maturation and delivery to synapses. It also interacts with PKCalpha and promotes wound healing. DLG1 is a member of the MAGUK (membrane-associated guanylate kinase) protein family, which is characterized by the presence of a core of three domains: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. DLG1 contains three PDZ domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 442628659 120 YMRALFTYNPSEDSLLPCRdiGLPFKSGDILQIINVKDPNWWQAKNITA--ESDKIGLIPSQELEE 183
Cdd:cd12031    4 YVRALFDYDKTKDSGLPSQ--GLNFKFGDILHVVNASDDEWWQARQVTAdgESEEIGVIPSKRRVE 67

Src Homology 3 domain of Disks Large homolog 2; DLG2, also called postsynaptic density-93 (PSD93) or Channel-associated protein of synapse-110 (chapsyn 110), is a scaffolding protein that clusters at synapses and plays an important role in synaptic development and plasticity. The DLG2 delta isoform binds inwardly rectifying potassium Kir2 channels, which determine resting membrane potential in neurons. It regulates the spatial and temporal distribution of Kir2 channels within neuronal membranes. DLG2 is a member of the MAGUK (membrane-associated guanylate kinase) protein family, which is characterized by the presence of a core of three domains: PDZ, SH3, and guanylate kinase (GuK). The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain. DLG2 contains three PDZ domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 442628659 115 KKLTCYMRALFTYNPSEDSLLPCRdiGLPFKSGDILQIINVKDPNWWQAKNITAE--SDKIGLIPSQELEERRK 186
Cdd:cd12032    2 QKRSLYVRAMFDYEKSKDSGLPSQ--GLSFRYGDILHVINASDDEWWQARRVTPDgdSEEMGVIPSKRRVERKE 73

guanylate kinase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659 243 KTLVLIGVSGVGRRTLKNRLINSDVDkFGAVIPHTSRPKRALEENGSSYWFMDREEMEEAVRNNEFLEYGEHNGNLYGTH 322
Cdd:PRK14737   5 KLFIISSVAGGGKSTIIQALLEEHPD-FLFSISCTTRAPRPGDEEGKTYFFLTIEEFKKGIADGEFLEWAEVHDNYYGTP 83

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 442628659 323 LQSIKDVINSGRMCILDCAPNALKILHNSQELMPFVIFVAAPGMEQ 368
Cdd:PRK14737  84 KAFIEDAFKEGRSAIMDIDVQGAKIIKEKFPERIVTIFIEPPSEEE 129

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659   119 CYMRALFTYNPSEDSllpcrdiGLPFKSGDILQIINVKDPNWWQAKNItaeSDKIGLIPS 178
Cdd:smart00326   3 PQVRALYDYTAQDPD-------ELSFKKGDIITVLEKSDDGWWKGRLG---RGKEGLFPS 52

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 442628659 120 YMRALFTYNPSEDSllpcrdiGLPFKSGDILQIINVKDPNWWQAKNitaESDKIGLIPS 178
Cdd:cd00174    1 YARALYDYEAQDDD-------ELSFKKGDIITVLEKDDDGWWEGEL---NGGREGLFPA 49

PDZ domain; PDZ domains are found in diverse signaling proteins.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 442628659   11 LRRDPSKPLGLTVELDEFKQ---LVVARILAGGVIDKQSmLHVGDVILEVNGTPVR--TPDELQVEVSRAKENLTLKI 83
Cdd:pfam00595   4 LEKDGRGGLGFSLKGGSDQGdpgIFVSEVLPGGAAEAGG-LKVGDRILSINGQDVEnmTHEEAVLALKGSGGKVTLTI 80

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442628659     6 IKMVGLRRDPsKPLGLTV--ELDEFKQLVVARILAGGVIDKQSmLHVGDVILEVNGTPVR--TPDELQVEVSRAKENLTL 81
Cdd:smart00228   2 PRLVELEKGG-GGLGFSLvgGKDEGGGVVVSSVVPGSPAAKAG-LRVGDVILEVNGTSVEglTHLEAVDLLKKAGGKVTL 79

                   ..
gi 442628659    82 KI 83
Cdd:smart00228  80 TV 81

PDZ domain of membrane palmitoylated protein 5 (MPP5), Drosophila Stardust, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of MPP5, Drosophila Stardust, and related domains. MPP5 (also known as MAGUK p55 subfamily member 1, protein associated with Lin-7 1 or PALS1) and Drosophila Stardust are membrane-associated guanylate kinase (MAGUK)-like proteins that serve as signaling and scaffolding proteins, linking different proteins critical to the formation and maintenance of tight junctions (TJ) and apical-basal polarity. Apical-basal polarity determinants cluster in complexes; in particular, the Crumbs complex (Crb, MPP5, and PATJ) and the PAR/aPKC-complex (PAR-3, PAR-6, aPKC) determine the apical plasma membrane domain. Within the Crumbs complex, Crb is stabilized in the plasma membrane by MPP5, which in turn recruits PATJ and Lin-7 to the complex. MPP5 also links the Crumbs complex with the PAR/aPKC-complex. The Drosophila homolog of the Crumbs complex is the (CRB)-Stardust (Sdt)-Discs Lost (Dlt) complex. MPP5 also acts as an interaction partner for SARS-CoV envelope protein E, which results in delayed formation of TJs and dysregulation of cell polarity. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This MPP5-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 442628659  17 KPLGLTVElDEFKQLVVARILAGGVIDKQSMLHVGDVILEVNGTPVR 63
Cdd:cd06798   10 EPLGATVR-NEGDSVIISRIVKGGAAEKSGLLHEGDEILEINGIEIR 55

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 442628659 120 YMRALFTYNPSEDSllpcrdiGLPFKSGDILQIINVKDPNWWQAKNItaesDKIGLIPS 178
Cdd:cd11949    1 YVQALFDFDPQEDG-------ELGFRRGDFIEVMDNSDPNWWKGACH----GQTGMFPR 48

C-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domains (SH3c) of the related proteins, GRB2 and GRAP2, have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 442628659 120 YMRALFTYNPSEDSllpcrdiGLPFKSGDILQIINVKDPNWWQAKNitaeSDKIGLIP 177
Cdd:cd11951    1 FVQAQYDFSAEDPS-------QLSFRRGDIIEVLDCPDPNWWRGRI----SGRVGFFP 47

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 442628659 122 RALFTYNPSEDSllpcrdiGLPFKSGDILQIINVKDPNWWQAKNitaeSDKIGLIPSQ 179
Cdd:cd11820    4 RALYDFEAAEDN-------ELTFKAGEIITVLDDSDPNWWKGSN----HRGEGLFPAN 50