FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains protein 3 (SHANK3); SHANK3, also termed proline-rich synapse-associated protein 2 (ProSAP2), is a postsynaptic density (PSD)-associated scaffolding protein at the excitatory synapse that interconnects neurotransmitter receptors and cell adhesion molecules by direct and indirect interactions with numerous other PSD-associated proteins. It is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. It is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic strength. Mutations in the SHANK3 synaptic scaffolding gene may lead to autism spectrum disorder and mental retardation, and the cause of human Phelan-McDermid syndrome (22q13.3 deletion syndrome) has been isolated to loss of function of one copy of the SHANK3 gene. SHANK3 contains an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also known as DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188  83 AVVVRVGIPDLQQTKCLRLDPTAPVWAAKQRVLCALNHSLQDALNYGLFQPPSRGRAGKFLDEERLLQDYPPNLDTPLPY 162
Cdd:cd17177     1 ALVVRIGIPDLQQTKCLRLNPDAPVWASKQRILCTLNHSLKDVLNYGLFQPAFNGRAGKFLDEERLLREYPLPLDTPVPY 80

                  ....*..
gi 1958791188 163 LEFRYKR 169
Cdd:cd17177    81 LEFRYKR 87

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 3; Shank3, also called ProSAP2 (Proline-rich synapse-associated protein 2), is widely expressed. It plays a role in the formation of dendritic spines and synapses. Haploinsufficiency of the Shank3 gene causes the 22q13 deletion/Phelan-McDermid syndrome, and variants of Shank3 have been implicated in autism spectrum disorder, schizophrenia, and intellectual disability. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. 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 1958791188 548 RKFIAVKAHSPQGEGEIPLHRGEAVKVLSIGEGGFWEGTVKGRTGWFPADCV 599
Cdd:cd11984     1 RTFIAVKAYSPQGEGEIQLNRGERVKVLSIGEGGFWEGTVKGRTGWFPADCV 52

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains protein 3 (SHANK3); SHANK3, also termed proline-rich synapse-associated protein 2 (ProSAP2), is a postsynaptic density (PSD)-associated scaffolding protein at the excitatory synapse that interconnects neurotransmitter receptors and cell adhesion molecules by direct and indirect interactions with numerous other PSD-associated proteins. It is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. It is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic strength. Mutations in the SHANK3 synaptic scaffolding gene may lead to autism spectrum disorder and mental retardation, and the cause of human Phelan-McDermid syndrome (22q13.3 deletion syndrome) has been isolated to loss of function of one copy of the SHANK3 gene. SHANK3 contains an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also known as DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188  83 AVVVRVGIPDLQQTKCLRLDPTAPVWAAKQRVLCALNHSLQDALNYGLFQPPSRGRAGKFLDEERLLQDYPPNLDTPLPY 162
Cdd:cd17177     1 ALVVRIGIPDLQQTKCLRLNPDAPVWASKQRILCTLNHSLKDVLNYGLFQPAFNGRAGKFLDEERLLREYPLPLDTPVPY 80

                  ....*..
gi 1958791188 163 LEFRYKR 169
Cdd:cd17177    81 LEFRYKR 87

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 3; Shank3, also called ProSAP2 (Proline-rich synapse-associated protein 2), is widely expressed. It plays a role in the formation of dendritic spines and synapses. Haploinsufficiency of the Shank3 gene causes the 22q13 deletion/Phelan-McDermid syndrome, and variants of Shank3 have been implicated in autism spectrum disorder, schizophrenia, and intellectual disability. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. 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 1958791188 548 RKFIAVKAHSPQGEGEIPLHRGEAVKVLSIGEGGFWEGTVKGRTGWFPADCV 599
Cdd:cd11984     1 RTFIAVKAYSPQGEGEIQLNRGERVKVLSIGEGGFWEGTVKGRTGWFPADCV 52

Ankyrin repeats (3 copies);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 329 IHQACRFGHVQHLEHLLFYGANMGAQNASGNTALHICALYNQESCARVLLfRGANKDVRNYNsQTAFQVAIIAGNFELAE 408
Cdd:pfam12796   1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLL-EHADVNLKDNG-RTALHYAARSGHLEIVK 78

                  ..
gi 1958791188 409 VI 410
Cdd:pfam12796  79 LL 80

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
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958791188  546 PGRKFIAVKAHSPQGEGEIPLHRGEAVKVLSIGEGGFWEGTVK-GRTGWFPADCVE 600
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGrGKEGLFPSNYVE 56

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 1958791188  651 RDHEGFGFVLRGAKAEtpieeftptpafPALQYLESVDVEGVAWKAGLRTGDFLIEVNGVNVVKVGHKQVVGLIRQGGNR 730
Cdd:smart00228   9 KGGGGLGFSLVGGKDE------------GGGVVVSSVVPGSPAAKAGLRVGDVILEVNGTSVEGLTHLEAVDLLKKAGGK 76

                   ....*.
gi 1958791188  731 LVMKVV 736
Cdd:smart00228  77 VTLTVL 82

N-terminal or F0 domain of Talin-head FERM; FERM_f0 forms a stable globular structure. The fold is an ubiquitin-like fold joined to the f1 domain in a novel fixed orientation by an extensive charged interface. It is required for maximal integrin-activation, by interacting with other FA components, No binding partner has yet been found for it.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1958791188  86 VRVGIPDLQQTKCLRLDPTAPVWAAKQRVLCALNHSLQDALNYGLFQPPSRGRAGKFLDEERLLQDYPPNLDTPLPY 162
Cdd:pfam16511   3 LKISIVGSNVTKTMQFDPSTTVYDACRLIREKIPEGGLNASEYGLFLADEDPKKGRWLEPGRTLEYYDLRNGDELEY 79

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains protein 3 (SHANK3); SHANK3, also termed proline-rich synapse-associated protein 2 (ProSAP2), is a postsynaptic density (PSD)-associated scaffolding protein at the excitatory synapse that interconnects neurotransmitter receptors and cell adhesion molecules by direct and indirect interactions with numerous other PSD-associated proteins. It is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. It is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic strength. Mutations in the SHANK3 synaptic scaffolding gene may lead to autism spectrum disorder and mental retardation, and the cause of human Phelan-McDermid syndrome (22q13.3 deletion syndrome) has been isolated to loss of function of one copy of the SHANK3 gene. SHANK3 contains an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also known as DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188  83 AVVVRVGIPDLQQTKCLRLDPTAPVWAAKQRVLCALNHSLQDALNYGLFQPPSRGRAGKFLDEERLLQDYPPNLDTPLPY 162
Cdd:cd17177     1 ALVVRIGIPDLQQTKCLRLNPDAPVWASKQRILCTLNHSLKDVLNYGLFQPAFNGRAGKFLDEERLLREYPLPLDTPVPY 80

                  ....*..
gi 1958791188 163 LEFRYKR 169
Cdd:cd17177    81 LEFRYKR 87

PDZ domain of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2, SHANK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SHANK1, SHANK2, SHANK3, and related domains. SHANK family proteins, SHANK1 (also known as somatostatin receptor-interacting protein, SSTR-interacting protein, SSTRIP), SHANK2 (also known as cortactin-binding protein 1, proline-rich synapse-associated protein 1), and SHANK3 (proline-rich synapse-associated protein 2) are synaptic scaffolding proteins which are highly enriched in the post-synaptic densities of excitatory synapses. They have been implicated in synaptic transmission, synapse formation, synaptic plasticity, and cytoskeletal remodeling, and are regulators of Cav1 calcium current and CREB target expression. Many protein ligands have been identified for the Shank PDZ domain, such as GKAP (also known as SAPAP), betaPIX (a guanine nucleotide exchange factor used by Rho GTPase family members Rac1 and Cdc42), alpha-latrotoxin, neuroligin, group I metabotropic glutamate receptors (mGluRs), and L-type calcium channels. 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 SHANK-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged as 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 1958791188 638 DYVIDDKVAILQKRDhEGFGFVLRGAKAETPIEEFTPTPAFPALQYLESVDVEGVAWKAGLRTGDFLIEVNGVNVVKVGH 717
Cdd:cd06746     1 DSIIDPRTVVLQKGD-KGFGFVLRGAKAVGPILEFTPTPAFPALQYLESVDPGGVADKAGLKKGDFLLEINGEDVVKASH 79

                          90       100
                  ....*....|....*....|..
gi 1958791188 718 KQVVGLIRQGGNRLVMKVVSVT 739
Cdd:cd06746    80 EQVVNLIRQSGNTLVLKVVTVT 101

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains protein 2 (SHANK2); SHANK2, also termed cortactin-binding protein 1 (CortBP1), or proline-rich synapse-associated protein 1, is a postsynaptic density (PSD)-associated scaffolding proteins at the excitatory synapse that interconnects neurotransmitter receptors and cell adhesion molecules by direct and indirect interactions with numerous other PSD-associated proteins. It is strongly expressed in the cerebellum. Moreover, SHANK2 acts as a component of the albumin endocytic pathway in podocytes, and regulates renal albumin endocytosis. It also associates with and regulates Na+/H+ exchanger 3 (NHE3) and is involved in the fine regulation of transepithelial salt and water transport through affecting NHE3 expression and activity. Mutations in the SHANK2 synaptic scaffolding gene may lead to autism spectrum disorder and mental retardation. SHANK2 contains an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also termed DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188  82 SAVVVRVGIPDLQQTKCLRLDPTAPVWAAKQRVLCALNHSLQDALNYGLFQPPSRGRAGKFLDEERLLQDYPPNLDTPLP 161
Cdd:cd17176     1 NTLVIRIIIPDLQQTKCIRFNPDATVWVAKQRILCTLNQSLKDVLNYGLFQPASNGRDGKFLDEERLLREYPQPVNKGVP 80

                  ....*...
gi 1958791188 162 YLEFRYKR 169
Cdd:cd17176    81 SLEFRYKK 88

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 155 NLDTPLPYLEFRYKRRVYAQNLIDDKQFAKLHTKANLKKFMDYVQLHSTDKVARLLDKGLDPNFHDPDSGECPLSLAAQL 234
Cdd:COG0666    18 LLLLALLLLAAALLLLLLLLLLLLLALLALALADALGALLLLAAALAGDLLVALLLLAAGADINAKDDGGNTLLHAAARN 97

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 235 DNaTDLLKVLRNGGAHLDFRTRDGLTAVHCATRQRNAGALTTLLDLGASPDYKDSRGLTPLyHSALGGGDALCCELLLHD 314
Cdd:COG0666    98 GD-LEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPL-HLAAANGNLEIVKLLLEA 175

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 315 HAQLGTTDENGWQEIHQACRFGHVQHLEHLLFYGANMGAQNASGNTALHICALYNQESCARVLLFRGANKDVRNYNSQTA 394
Cdd:COG0666   176 GADVNARDNDGETPLHLAAENGHLEIVKLLLEAGADVNAKDNDGKTALDLAAENGNLEIVKLLLEAGADLNAKDKDGLTA 255

                         250
                  ....*....|....
gi 1958791188 395 FQVAIIAGNFELAE 408
Cdd:COG0666   256 LLLAAAAGAALIVK 269

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 175 NLIDDKQFAKLHTKANLKKFMDYVQLHSTDKVARLLDKGLDPNFHDPDSGecPLSLAAQLDNATDLLKVLRNGGAHLDFR 254
Cdd:COG0666     6 LLLLLLLAALLLLLLLALLLLAAALLLLLLLLLLLLLALLALALADALGA--LLLLAAALAGDLLVALLLLAAGADINAK 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 255 TRDGLTAVHCATRQRNAGALTTLLDLGASPDYKDSRGLTPLYHSALGGGDALCcELLLHDHAQLGTTDENGWQEIHQACR 334
Cdd:COG0666    84 DDGGNTLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIV-KLLLEAGADVNAQDNDGNTPLHLAAA 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 335 FGHVQHLEHLLFYGANMGAQNASGNTALHICALYNQESCARVLLFRGANKDVRNYNSQTAFQVAIIAGNFELAEVIKTHK 414
Cdd:COG0666   163 NGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEIVKLLLEAGADVNAKDNDGKTALDLAAENGNLEIVKLLLEAG 242

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 2; Shank2, also called ProSAP1 (Proline-rich synapse-associated protein 1) or CortBP1 (Cortactin-binding protein 1), is found in neurons, glia, endocrine cells, liver, and kidney. It plays a role in regulating dendritic spine volume and branching and postsynaptic clustering. Mutations in the Shank2 gene are associated with autism spectrum disorder and mental retardation. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. 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 1958791188 548 RKFIAVKAHSPQGEGEIPLHRGEAVKVLSIGEGGFWEGTVKGRTGWFPADCV 599
Cdd:cd11983     1 RHFVVVKSYQPQVEGEIPLHKGDRVKVLSIGEGGFWEGSARGHVGWFPAECV 52

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 239 DLLKVLRNGGAHLDFRTRDGLTAVHCATRQRNAGALTTLLDLGASPDYKDSRGLTPLYHSALGGGDALCCELLLHDHAQL 318
Cdd:COG0666     1 LLLLLLLLLLLLAALLLLLLLALLLLAAALLLLLLLLLLLLLALLALALADALGALLLLAAALAGDLLVALLLLAAGADI 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 319 GTTDENGWQEIHQACRFGHVQHLEHLLFYGANMGAQNASGNTALHICALYNQESCARVLLFRGANKDVRNYNSQTAFQVA 398
Cdd:COG0666    81 NAKDDGGNTLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLA 160

                         170
                  ....*....|
gi 1958791188 399 IIAGNFELAE 408
Cdd:COG0666   161 AANGNLEIVK 170

Variant 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 1958791188 549 KFIAVKAHSPQGEGEIPLHRGEAVKVLSIGEGGFWEGTVKGRTGWFPADCVEEV 602
Cdd:pfam07653   1 YGRVIFDYVGTDKNGLTLKKGDVVKVLGKDNDGWWEGETGGRVGLVPSTAVEEI 54

PDZ domain of sorting nexin-27 (SNX27), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SNX27, and related domains. SNX27 is involved in retrograde transport from endosome to plasma membrane. The PDZ domain of SNX27 links cargo identification to retromer-mediated transport. SNX27 binds to the retromer complex (vacuolar protein sorting 26(VPS26)-VPS29-VPS35), via its PDZ domain binding to VPS26. The SNX27 PDZ domain also binds to cargo including the G-protein-coupled receptors (GPCRs): beta2-adrenergic receptor (beta2AR), beta1AR, parathyroid hormone receptor (PTHR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), NMDA receptors, 5-hydroxytryptamine 4a receptors, frizzled receptors, and somatostatin receptor subtype 5 (SSTR5). Additional binding partners of the SNX27 PDZ domain include G protein-gated inwardly rectifying potassium (Kir3) channels, angiotensin-converting enzyme 2 (ACE2), and PTEN (phosphatase and tensin homolog deleted on chromosome 10); PTEN binding to SNX27 prevents SNX27's association with the retromer complex. SNX27 has been reported to be a host factor needed for efficient entry of an engineered SARS-CoV-2 variant, the spike protein of which contains a deletion at the S1/S2 subunit cleavage site; the PDZ domain of SNX27 binds angiotensin-converting enzyme 2 (ACE2), and may be involved in recycling ACE2 to the plasma membrane, thereby promoting viral entry. 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 SNX27-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 1958791188 650 KRDHEGFGFVLRGAKAETPIEEFTPTPAFPALQYLESVDVEGVAWKAGLRTGDFLIEVNGVNVVKVGHKQVVGLIRQGGN 729
Cdd:cd23070     6 VKSETGFGFNVRGQVSEGGQLRSINGELYAPLQHVSAVLEGGAADKAGVRKGDRILEVNGVNVEGATHKQVVDLIKSGGD 85

                  ....*...
gi 1958791188 730 RLVMKVVS 737
Cdd:cd23070    86 ELTLTVIS 93

ankyrin-like protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 204 DKVARLLDKGLDPNFHDPdSGECPLS--LAAQLDNATDLLKVLRNGGAHLDFRTRDGLTAVHCATRQRN-AGALTTLLDL 280
Cdd:PHA03095   28 EEVRRLLAAGADVNFRGE-YGKTPLHlyLHYSSEKVKDIVRLLLEAGADVNAPERCGFTPLHLYLYNATtLDVIKLLIKA 106

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 281 GASPDYKDSRGLTPLyHSALGGG--DALCCELLLHDHAQLGTTDENGWQEIHQACRFGHV-------------------- 338
Cdd:PHA03095  107 GADVNAKDKVGRTPL-HVYLSGFniNPKVIRLLLRKGADVNALDLYGMTPLAVLLKSRNAnvellrllidagadvyavdd 185

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 339 -------QHLE----------HLLFYGANMGAQNASGNTALHICALYNqeSCARVLLF----RGANKDVRNYNSQTAFQV 397
Cdd:PHA03095  186 rfrsllhHHLQsfkprarivrELIRAGCDPAATDMLGNTPLHSMATGS--SCKRSLVLplliAGISINARNRYGQTPLHY 263

                  ....*.
gi 1958791188 398 AIIAGN 403
Cdd:PHA03095  264 AAVFNN 269

PDZ domains of the Na+/H+ exchange regulatory cofactor (NHERF) family (NHERF1-4), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of the Na+/H+ exchange regulatory cofactor (NHERF) family of multi-PDZ-domain-containing scaffolding proteins (NHERF1-4), and related domains. The NHERF family includes NHERF1 (also known as EBP50), NHERF2 (also known as E3KARP; TKA-1; SIP-1), NHERF3 (also known as CAP70; CLAMP; Napi-Cap-1; PDZD1) and NHERF4 (also known as IKEPP; PDZK2; Napi-Cap-2). NHERF1 and NHERF2 have tandem PDZ domains (PDZ1-2); NHERF3 and NHERF4 have four PDZ domains (PDZ1-4). NHERFs are involved in the regulation of multiple receptors or transporters, such as type II sodium-phosphate cotransporter (Npt2a), purinergic P2Y1 receptor P2Y1R, the beta2-adrenergic receptor (beta2-AR), parathyroid hormone receptor type 1 (PTHR), the lysophosphatidic acid receptors (LPARs), sodium-hydrogen exchanger 3 (NHE3), and cystic fibrosis transmembrane conductance regulator (CFTR). NHERF-PDZ1 domain interaction partners include Npt2a, purinergic P2Y1 receptor, beta2-AR, CFTR, PTHR, NH3, G-protein-coupled receptor kinase 6 (GRK6A), platelet-derived growth factor receptor (PDGFR), B1 subunit of the H+ATPase, cholesterol, receptor for activated C-kinase RACK1, aquaporin 9, among others. The NHERF PDZ2 domain interacts with fewer proteins: NHERF1 PDZ2 binds Npt2a, PTHR, beta-catenin, aquaporin 9, and RACK1; NHERF2 PDZ2 binds LPA2, P2Y1R, and NHE3, cGMP-dependent protein kinase type II (cGKII). NHERF4 PDZ1 and PDZ4 bind the epithelial Ca(2+) channels TRPV5 and TRPV6. NHERF2/NHERF3 heterodimerization is mediated by PDZ domains of NHERF2 and the C-terminal PDZ domain recognition motif of NHERF3. NHERF4 regulates several transporters mediating influx of xenobiotics and nutrients in the small intestine. 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 NHERF-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 1958791188 648 LQKRDhEGFGFVLRGAKAETpieeftptpafpaLQYLESVDVEGVAWKAGLRTGDFLIEVNGVNVVKVGHKQVVGLIRQG 727
Cdd:cd06768     5 LVKGP-EGYGFNLHAEKGRP-------------GHFIREVDPGSPAERAGLKDGDRLVEVNGENVEGESHEQVVEKIKAS 70

                          90
                  ....*....|
gi 1958791188 728 GNRLVMKVVS 737
Cdd:cd06768    71 GNQVTLLVVD 80

ankyrin repeat protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 204 DKVARLLDKGLDPNFHDPDSgECPLSLAAQLD-NATD---LLKVLRNGGAHLDFRTRDGLTAVHCA--TRQRNAGALTTL 277
Cdd:PHA03100   49 DVVKILLDNGADINSSTKNN-STPLHYLSNIKyNLTDvkeIVKLLLEYGANVNAPDNNGITPLLYAisKKSNSYSIVEYL 127

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 278 LDLGASPDYKDSRGLTPLyHSALGGG-----------------DALC-CELLLHDHAQLGTTDENGWQEIHQACRFGHVQ 339
Cdd:PHA03100  128 LDNGANVNIKNSDGENLL-HLYLESNkidlkilkllidkgvdiNAKNrVNYLLSYGVPINIKDVYGFTPLHYAVYNNNPE 206

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1958791188 340 HLEHLLFYGANMGAQNASGNTALHICALYNQESCARVLLFRGAN-KDVRNY 389
Cdd:PHA03100  207 FVKYLLDLGANPNLVNKYGDTPLHIAILNNNKEIFKLLLNNGPSiKTIIET 257

Src Homology 3 domain of beta-Pak Interactive eXchange factor; Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. 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
                  ....*....|....*....|....*....|....*....|..
gi 1958791188 561 EGEIPLHRGEAVKVLSIGEGGFWEGTVKGRTGWFPADCVEEV 602
Cdd:cd12061    13 EDELSFSKGDVIHVTRVEEGGWWEGTHNGRTGWFPSNYVREI 54

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 1958791188 549 KFIAVKAHSPQGEGEIPLHRGEAVKVLSIGEGGFWEGTV-KGRTGWFPADC 598
Cdd:cd00174     1 YARALYDYEAQDDDELSFKKGDIITVLEKDDDGWWEGELnGGREGLFPANY 51

ankyrin repeat protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 184 KLHTK-ANLKKFMDY-VQLHSTDKVARLLDKGLDPNFHDpDSGECPLSLAAQlDNATDLLKVLRNGGAHLDFRTRDGLTA 261
Cdd:PHA02874  116 DVNIKdAELKTFLHYaIKKGDLESIKMLFEYGADVNIED-DNGCYPIHIAIK-HNFFDIIKLLLEKGAYANVKDNNGESP 193

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 262 VHCATRQRNAGALTTLLDLGASPDYKDSRGLTPLYHSALGGGDALccELLLhDHAQLGTTDENGWQEIHQACRFG-HVQH 340
Cdd:PHA02874  194 LHNAAEYGDYACIKLLIDHGNHIMNKCKNGFTPLHNAIIHNRSAI--ELLI-NNASINDQDIDGSTPLHHAINPPcDIDI 270

                         170       180
                  ....*....|....*....|....*...
gi 1958791188 341 LEHLLFYGANMGAQNASGNTALHICALY 368
Cdd:PHA02874  271 IDILLYHKADISIKDNKGENPIDTAFKY 298

Ankyrin repeats (3 copies);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 194 FMDYVQLHSTDKVARLLDKGLDPNFHDPDsGECPLSLAAQLDNaTDLLKVLRNggaHLDFRTRD-GLTAVHCATRQRNAG 272
Cdd:pfam12796   1 LHLAAKNGNLELVKLLLENGADANLQDKN-GRTALHLAAKNGH-LEIVKLLLE---HADVNLKDnGRTALHYAARSGHLE 75

                          90
                  ....*....|....*.
gi 1958791188 273 ALTTLLDLGASPDYKD 288
Cdd:pfam12796  76 IVKLLLEKGADINVKD 91

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. 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
                  ....*....|....*....|....*....|....*....|....*...
gi 1958791188 549 KFIAVKAHSPQGEGEIPLHRGEAVKVLSIGEGGFWEGTVKGRTGWFPA 596
Cdd:cd11856     1 SYVAIADYEAQGDDEISLQEGEVVEVLEKNDSGWWYVRKGDKEGWVPA 48

ankyrin repeat protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 198 VQLHSTDKVARLLDKGLDPnfhdpdsgecplSLAAQLDNATDLLKVLRNGGAHLDFRTRDGLTAVHCATRQRNAGALTTL 277
Cdd:PHA02874   76 IKIGAHDIIKLLIDNGVDT------------SILPIPCIEKDMIKTILDCGIDVNIKDAELKTFLHYAIKKGDLESIKML 143

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 278 LDLGASPDYKDSRGLTPLyHSALGGGDALCCELLLHDHAQLGTTDENGWQEIHQACRFGHVQHLEHLLFYGANMGAQNAS 357
Cdd:PHA02874  144 FEYGADVNIEDDNGCYPI-HIAIKHNFFDIIKLLLEKGAYANVKDNNGESPLHNAAEYGDYACIKLLIDHGNHIMNKCKN 222

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|..
gi 1958791188 358 GNTALHICALYNQESCArvLLFRGANKDVRNYNSQTAFQVAI 399
Cdd:PHA02874  223 GFTPLHNAIIHNRSAIE--LLINNASINDQDIDGSTPLHHAI 262

Voltage-dependent potassium channel; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 236 NATDLLkvLRNGGAHLDFRTRDGLTAVhcaTRQRNAGALTTLLDLGASPDYKDSRGLTPLyHSALGGGDALCCELLLHDH 315
Cdd:PLN03192  508 NVGDLL--GDNGGEHDDPNMASNLLTV---ASTGNAALLEELLKAKLDPDIGDSKGRTPL-HIAASKGYEDCVLVLLKHA 581

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 316 AQLGTTDENGWQEIHQACRFGHvQHLEHLLFYGANMGAQNASGNTaLHICALYNQESCARVLLFRGANKDVRNYNSQTAF 395
Cdd:PLN03192  582 CNVHIRDANGNTALWNAISAKH-HKIFRILYHFASISDPHAAGDL-LCTAAKRNDLTAMKELLKQGLNVDSEDHQGATAL 659

                         170       180       190
                  ....*....|....*....|....*....|...
gi 1958791188 396 QVAIIAGNFEL--------AEVIKTHKDSDVVP 420
Cdd:PLN03192  660 QVAMAEDHVDMvrllimngADVDKANTDDDFSP 692

ankyrin repeat protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 172 YAQNLIDDKQFAKLHTKanlkkfmdyVQLHSTDK-VARLLDKGLDPNFHDPdSGECPLSLAAQLDNATDLLKVLRNGGAH 250
Cdd:PHA02876  264 FSVNSIDDCKNTPLHHA---------SQAPSLSRlVPKLLERGADVNAKNI-KGETPLYLMAKNGYDTENIRTLIMLGAD 333

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958791188 251 LDFRTRDGLTAVHCA-TRQRNAGALTTLLDLGASPDYKDSRGLTPLYHSALgGGDALCCELLLHDHAQLGTTDENGWQEI 329
Cdd:PHA02876  334 VNAADRLYITPLHQAsTLDRNKDIVITLLELGANVNARDYCDKTPIHYAAV-RNNVVIINTLLDYGADIEALSQKIGTAL 412

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1958791188 330 HQA-CRFGHVQHLEHLLFYGANMGAQNASGNTALHICALYN-QESCARVLLFRGANKDVRNYNSQTAFQVAI 399
Cdd:PHA02876  413 HFAlCGTNPYMSVKTLIDRGANVNSKNKDLSTPLHYACKKNcKLDVIEMLLDNGADVNAINIQNQYPLLIAL 484