ubiquitin-like (Ubl) domain found in heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1) and similar proteins; HOIL-1, also termed RBCK1, or HOIL-1L, or RanBP-type and C3HC4-type zinc finger-containing protein 1, HBV-associated factor 4, or Hepatitis B virus X-associated protein 4, or RING finger protein 54 (RNF54), or ubiquitin-conjugating enzyme 7-interacting protein 3, or UbcM4-interacting protein 28 (UIP28), together with E3 ubiquitin-protein ligase RNF31 (also known as HOIP) and SHANK-associated RH domain interacting protein (SHARPIN), forms the E3-ligase complex (also known as linear-ubiquitin-chain assembly complex LUBAC) that regulates NF-kappaB activity and apoptosis through conjugation of linear polyubiquitin chains to NF-kappaB essential modulator (also known as NEMO or IKBKG). HOIL-1 plays a crucial role in TNF-alpha-mediated NF-kappaB activation. It also functions as an ubiquitin-protein ligase E3 that interacts with not only PKCbeta but also PKCzeta. It can recognize heme-oxidized IRP2 (iron regulatory protein2) and is thought to affect the turnover of oxidatively damaged proteins. HOIL-1 contains an N-terminal ubiqutin-like (UBL) domain and an Npl4 zinc-finger (NZF) domain, which regulate the interaction with the LUBAC subunit RNF31 and ubiquitin, respectively. The NZF domain belongs to RanBP2-type zinc finger (zf-RanBP2) domain superfamily. In addition, HOIL-1 has a RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain use an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 165377121 215 PIRLQVTVEDATSVLSSSSSahvslKIHPHCSIAALQDQVFSEFGFPPAVQRWVIGRCLCMPERSLASYGVSQDGDPAFL 294
Cdd:cd01799    2 EISIKVYVEDKSSSSGPITL-----KVRPHTTIASLKRQIFLEYGFPPSVQRWIIGKRLATDDETLLSYGIKDSGDPAFL 76

                 ....*
gi 165377121 295 YLLSA 299
Cdd:cd01799   77 YLVSA 81

SHANK-associated RH domain interacting protein Pleckstrin homology (PH) domain; SHARPIN has a variety of roles including: a role as a scaffolding partner of anchoring/scaffold proteins Shank1, a role in carcinogenesis through the interaction with FYN binding protein (FYB), which binds to oncogene FYN, a role in apoptosis by interacting with AIFM1, a mitochondrial regulator of cell death, CAPN13, and NSD1, as well as a role in immune disease and inflammation. SHARPIN has at its N-terminus a PH domain, followed by a E3 ubiquitin ligase domain, and a C-terminal RanBP-type and C3HC4-type zinc finger containing 1 domain (RBCK1, also known as HOIP which functions as a protein kinase C (PKC) binding protein as well as a transcriptional activator. SHARPIN's PH domain functions as a dimerization module, rather than a ligand recognition domain. Instead it acts as a dimerization module extending the functional applications of this superfold. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 165377121  18 VVLLAVHAAVRPLGAG-QDAEAQPRKLQLIADPERPGRFRLGLLGTE---PGAVSLEWPLEAICYTVRGPNQHELQPPPG 93
Cdd:cd13305    2 VEEAVVHSEVRPLGPGsPPAPDGLLRLQLSADPARPGRFRLALQGAGdsgPPGEGLEWPLKSVSYEVKTPTCHELQPPKP 81

                         90       100       110
                 ....*....|....*....|....*....|...
gi 165377121  94 GPGTFSVHFLDPEEAQQWAALVRDATAEGQNGS 126
Cdd:cd13305   82 PPDALSFHFQDEQEAQRWATVVERALREAQRGT 114

Zn-finger in Ran binding protein and others;

                          10        20
                  ....*....|....*....|....*
gi 165377121  345 WSCPSCTFINASNRPGCEMCSTQRP 369
Cdd:pfam00641   5 WDCSKCLVQNFATSTKCVACQAPKP 29

SHANK-associated RH domain interacting protein Pleckstrin homology (PH) domain; SHARPIN has a variety of roles including: a role as a scaffolding partner of anchoring/scaffold proteins Shank1, a role in carcinogenesis through the interaction with FYN binding protein (FYB), which binds to oncogene FYN, a role in apoptosis by interacting with AIFM1, a mitochondrial regulator of cell death, CAPN13, and NSD1, as well as a role in immune disease and inflammation. SHARPIN has at its N-terminus a PH domain, followed by a E3 ubiquitin ligase domain, and a C-terminal RanBP-type and C3HC4-type zinc finger containing 1 domain (RBCK1, also known as HOIP which functions as a protein kinase C (PKC) binding protein as well as a transcriptional activator. SHARPIN's PH domain functions as a dimerization module, rather than a ligand recognition domain. Instead it acts as a dimerization module extending the functional applications of this superfold. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 165377121  18 VVLLAVHAAVRPLGAG-QDAEAQPRKLQLIADPERPGRFRLGLLGTE---PGAVSLEWPLEAICYTVRGPNQHELQPPPG 93
Cdd:cd13305    2 VEEAVVHSEVRPLGPGsPPAPDGLLRLQLSADPARPGRFRLALQGAGdsgPPGEGLEWPLKSVSYEVKTPTCHELQPPKP 81

                         90       100       110
                 ....*....|....*....|....*....|...
gi 165377121  94 GPGTFSVHFLDPEEAQQWAALVRDATAEGQNGS 126
Cdd:cd13305   82 PPDALSFHFQDEQEAQRWATVVERALREAQRGT 114

ubiquitin-like (Ubl) domain found in ubiquitin and ubiquitin-like Ubl proteins; Ubiquitin-like (Ubl) proteins have a similar ubiquitin (Ub) beta-grasp fold and attach to other proteins in a Ubl manner but with biochemically distinct roles. Ub and Ubl proteins conjugate and deconjugate via ligases and peptidases to covalently modify target polypeptides. Some Ubl domains have adaptor roles in Ub-signaling by mediating protein-protein interaction. Prokaryotic sulfur carrier proteins are Ub-related proteins that can be activated in an ATP-dependent manner. Polyubiquitination signals for a diverse set of cellular events via different isopeptide linkages formed between the C terminus of one ubiquitin (Ub) and the epsilon-amine of K6, K11, K27, K29, K33, K48, or K63 of a second Ub. One of these seven lysine residues (K27, Ub numbering) is conserved in this Ubl_ubiquitin_like family. K27-linked Ub chains are versatile and can be recognized by several downstream receptor proteins. K27 has roles beyond chain linkage, such as in Ubl NEDD8 (which contains many of the same lysines (K6, K11, K27, K33, K48) as Ub) where K27 has a role (other than conjugation) in the mechanism of protein neddylation.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 165377121 240 KIHPHCSIAALQDQVFSEFGFPPAVQRWVIGRCLCMPERSLASYGVsQDGDPAFLY 295
Cdd:cd17039   14 EVDPDDTVADLKEKIEEKTGIPVEQQRLIYNGKELKDDKTLSDYGI-KDGSTIHLV 68

Zinc finger domain; Zinc finger domain in Ran-binding proteins (RanBPs), and other proteins. In RanBPs, this domain binds RanGDP.

                           10        20
                   ....*....|....*....|..
gi 165377121   345 WSCPSCTFINASNRPGCEMCST 366
Cdd:smart00547   3 WECPACTFLNFASRSKCFACGA 24