RING finger (Really Interesting New Gene) domain and U-box domain superfamily; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enable efficient transfer of ubiquitin from E2 to the substrates.

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gi 1907150329   1 MCPLGKMRLTVPCRALTCAHLQSFDAALYLQMNEKKPTWTCPVCDKKAPYESLII 55
Cdd:cd16820     8 MCPLGKMRLTVPCRAITCTHLQCFDAALYLQMNEKKPTWTCPVCDKKAPYESLII 62

SP-RING finger found in protein inhibitor of activated STAT protein 3 (PIAS3) and similar proteins; PIAS3 is an E3 SUMO-protein ligase that was initially identified as an interleukin-6 (IL-6)-dependent repressor of signal transducer and activator of transcription 3 (STAT3) and has anti-proliferative properties. It binds specifically to phosphorylated STAT3 and inhibits its transcriptional activity by blocking its binding to DNA. It regulates STAT3-mediated induction of Snail expression, as well as suppresses acute graft-versus-host disease (GVHD) by modulating effector T and B cell subsets through inhibition of STAT3 activation. It activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status. When overexpressed, it can interact with STAT5 to regulate prolactin-induced STAT5-mediated gene expression. Moreover, PIAS3 binds to and activates Smad3 transcriptional activity, resulting in the enhancement of transforming growth factor-beta (TGF-beta) signaling. It functions as a transcriptional corepressor of Erythroid Kruppel-like factor (EKLF or KLF1) and thus plays an important role in erythropoiesis. It also plays a significant role in the DNA damage response (DDR) pathway by promoting homologous recombination (HR)- and non-homologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair. Furthermore, PIAS3 preferentially interacts with and enhances the SUMOylation of TAK1-binding protein 2 (TAB2), an upstream adaptor protein in the IL-1 signaling pathway. It also promotes SUMOylation and nuclear sequestration of ErbB4 receptor tyrosine kinase. In addition, PIAS3 may form a complex with microphthalmia-associated transcription factor, nuclear factor-kappaB, Smad, and estrogen receptor. Its other transcription factor binding partners include: ETS, EGR1, NR1I2, and GATA1. PIAS3 contains an N-terminal SAP (scaffold attachment factor A/B (SAF-A/B), acinus and PIAS) box with the LXXLL signature, a PINT motif, a specific RING finger known as Siz/PIAS (protein inhibitor of activated signal transducer and activator of transcription) RING (SP-RING) finger, and an acidic C-terminal domain. The SP-RING finger is a variant of RING finger, which lacks the second, fifth, and sixth zinc-binding residues of the consensus C3H2C3-/C3HC4-type RING fingers. It binds a single Zn ion, instead of two ions bound by typical RING fingers.

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gi 1907150329   1 MCPLGKMRLTVPCRALTCAHLQSFDAALYLQMNEKKPTWTCPVCDKKAPYESLII 55
Cdd:cd16820     8 MCPLGKMRLTVPCRAITCTHLQCFDAALYLQMNEKKPTWTCPVCDKKAPYESLII 62

SP-RING finger found in protein inhibitor of activated STAT protein 3 (PIAS3) and similar proteins; PIAS3 is an E3 SUMO-protein ligase that was initially identified as an interleukin-6 (IL-6)-dependent repressor of signal transducer and activator of transcription 3 (STAT3) and has anti-proliferative properties. It binds specifically to phosphorylated STAT3 and inhibits its transcriptional activity by blocking its binding to DNA. It regulates STAT3-mediated induction of Snail expression, as well as suppresses acute graft-versus-host disease (GVHD) by modulating effector T and B cell subsets through inhibition of STAT3 activation. It activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status. When overexpressed, it can interact with STAT5 to regulate prolactin-induced STAT5-mediated gene expression. Moreover, PIAS3 binds to and activates Smad3 transcriptional activity, resulting in the enhancement of transforming growth factor-beta (TGF-beta) signaling. It functions as a transcriptional corepressor of Erythroid Kruppel-like factor (EKLF or KLF1) and thus plays an important role in erythropoiesis. It also plays a significant role in the DNA damage response (DDR) pathway by promoting homologous recombination (HR)- and non-homologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair. Furthermore, PIAS3 preferentially interacts with and enhances the SUMOylation of TAK1-binding protein 2 (TAB2), an upstream adaptor protein in the IL-1 signaling pathway. It also promotes SUMOylation and nuclear sequestration of ErbB4 receptor tyrosine kinase. In addition, PIAS3 may form a complex with microphthalmia-associated transcription factor, nuclear factor-kappaB, Smad, and estrogen receptor. Its other transcription factor binding partners include: ETS, EGR1, NR1I2, and GATA1. PIAS3 contains an N-terminal SAP (scaffold attachment factor A/B (SAF-A/B), acinus and PIAS) box with the LXXLL signature, a PINT motif, a specific RING finger known as Siz/PIAS (protein inhibitor of activated signal transducer and activator of transcription) RING (SP-RING) finger, and an acidic C-terminal domain. The SP-RING finger is a variant of RING finger, which lacks the second, fifth, and sixth zinc-binding residues of the consensus C3H2C3-/C3HC4-type RING fingers. It binds a single Zn ion, instead of two ions bound by typical RING fingers.

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gi 1907150329   1 MCPLGKMRLTVPCRALTCAHLQSFDAALYLQMNEKKPTWTCPVCDKKAPYESLII 55
Cdd:cd16820     8 MCPLGKMRLTVPCRAITCTHLQCFDAALYLQMNEKKPTWTCPVCDKKAPYESLII 62

SP-RING finger found in protein inhibitor of activated signal transducer and activator of transcription (PIAS) proteins; The PIAS (protein inhibitor of activated STAT) protein family modulates the activity of several transcription factors and acts as an E3 ubiquitin ligase in the sumoylation pathway. It consists of four members: PIAS1, PIAS2 (also known as PIASx), PIAS3, and PIAS4 (also known as PIASy). PIAS proteins were initially identified as inhibitors of activated STAT only, but are now known to interact with and modulate several other proteins, including androgen receptor (AR), tumor suppressor p53, and the transforming growth factor-beta (TGF-beta) signaling protein SMAD. They interact with STATs in a cytokine-dependent manner. PIAS1, PIAS2, and PIAS3 interact with STAT1, STAT3, and STAT4, respectively. In addition, PIAS4 is associated with STAT1. PIAS proteins have SUMO E3-ligase activity and interaction of PIAS proteins with transcription factors often results in sumoylation of that protein. PIAS proteins contain an N-terminal SAP (scaffold attachment factor A/B (SAF-A/B), acinus and PIAS) box with the LXXLL signature, which is required for the trans-repression of STAT1 activity by PIAS2, a PINT motif, which is essential for nuclear retention of PIAS3L (the long form of PIAS3), a specific RING finger known as Siz/PIAS (protein inhibitor of activated signal transducer and activator of transcription) RING (SP-RING) finger, which is essential for SUMO ligase activity, and the acidic C-terminal domain, which is involved in binding of PIAS3 to the nuclear coactivator TIF2. The SP-RING finger is a variant of RING finger, which lacks the second, fifth, and sixth zinc-binding residues of the consensus C3H2C3-/C3HC4-type RING fingers. It binds a single Zn ion, instead of two ions bound by typical RING fingers.

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gi 1907150329   1 MCPLGKMRLTVPCRALTCAHLQSFDAALYLQMNEKKPTWTCPVCDK 46
Cdd:cd16790     3 MCPLGKMRLTIPCRALTCSHLQCFDAALYLQMNEKKPTWICPVCDK 48

SP-RING finger found in protein inhibitor of activated STAT protein 4 (PIAS4) and similar proteins; PIAS4, also known as PIASy or protein inhibitor of activated STAT protein gamma (PIAS-gamma), is an E3 SUMO-protein ligase that interacts with the androgen receptor (AR) and is involved in ubiquitin signaling pathways. It is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome. It also regulates the hypoxia signalling pathway by interacting with the tumor suppressor von Hippel-Lindau (VHL), which leads to VHL sumoylation, oligomerization, and impaired function during growth of pancreatic cancer cells. Moreover, PIAS4 acts as a direct binding partner for vitamin D receptor (VDR) and facilitates its modification with SUMO2. The process of SUMOylation modulates VDR-mediated signaling. As components of the DNA-damage response (DDR), PIAS4 together with PIAS1 promote responses to DNA double-strand breaks (DSBs). They are required for effective ubiquitin-adduct formation mediated by RNF8, RNF168, and BRCA1 at sites of DNA damage. PIAS4 contains an N-terminal SAP (scaffold attachment factor A/B (SAF-A/B), acinus and PIAS) box with the LXXLL signature, a PINT motif, a specific RING finger known as Siz/PIAS (protein inhibitor of activated signal transducer and activator of transcription) RING (SP-RING) finger, and an acidic C-terminal domain. The SP-RING finger is a variant of RING finger, which lacks the second, fifth, and sixth zinc-binding residues of the consensus C3H2C3-/C3HC4-type RING fingers. It binds a single Zn ion, instead of two ions bound by typical RING fingers.

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gi 1907150329   1 MCPLGKMRLTVPCRALTCAHLQSFDAALYLQMNEKKPTWTCPVCDKKAPYE 51
Cdd:cd16821     8 ICPLVKMRLSVPCRAETCAHLQCFDAVFYLQMNEKKPTWTCPVCDKPAPYD 58

MIZ/SP-RING zinc finger; This domain has SUMO (small ubiquitin-like modifier) ligase activity and is involved in DNA repair and chromosome organization.

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gi 1907150329   2 CPLGKMRLTVPCRALTCAHLQSFDAALYLQMNEKKPTWTCPVCDK 46
Cdd:pfam02891   5 CPISYLRISIPVRGRFCKHLQCFDLLSYLESNERTPTWNCPVCDK 49

SP-RING finger found in zinc finger MIZ domain-containing protein 1 (Zmiz1) and similar proteins; Zmiz1, also known as PIAS-like protein Zimp10 (zinc finger-containing, Miz1, PIAS-like protein on chromosome 10) or retinoic acid-induced protein 17, is a novel PIAS-like protein that was initially identified as an androgen receptor (AR) interacting protein and functions as a transcriptional co-activator. It co-localizes with AR and small ubiquitin-like modifier SUMO-1, forms a protein complex at replication foci in the nucleus, and augments AR-mediated transcription. It also functions as a transcriptional co-activator of the p53 tumor suppressor that plays a critical role in cell cycle progression, DNA repair, and apoptosis. Moreover, Zmiz1 dysfunction may be associated with multiple autoimmune diseases and it has been implicated in the development, function, and survival of melanocytes. Zmiz1 also interacts with Smad3/4 proteins and augments Smad-mediated transcription, suggesting it is important in the regulation of the transforming growth factor beta (TGF-beta)/Smad signaling pathway and may have an inhibitory effect on the immune system. Zmiz1 is overexpressed in a significant percentage of human cutaneous squamous cell carcinoma (SCC), breast, ovarian, and colon cancers, suggesting it may play a broader role in epithelial cancers. It functionally interacts with NOTCH1 to promote C-MYC transcription and activity, and thus is involved in a variety of C-MYC-driven cancers. Zmiz1 contains a PAT domain, a highly conserved Siz/PIAS (protein inhibitor of activated signal transducer and activator of transcription) RING (SP-RING) finger, also known as msx-interacting zinc finger (Miz domain), and a putative nuclear localization sequence (NLS), as well as a strong intrinsic transactivation domain within the C-terminus. The SP-RING finger is a variant of RING finger, which lacks the second, fifth, and sixth zinc-binding residues of the consensus C3H2C3-/C3HC4-type RING fingers. It binds a single Zn ion, instead of two ions bound by typical RING fingers.

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gi 1907150329   2 CPLGKMRLTVPCRALTCAHLQSFDAALYLQMNEKKPTWTCPVCDKKAPYESLIID 56
Cdd:cd16822     6 CPITFRRIQLPARGHDCKHVQCFDLESYLQLNCERGTWRCPVCNKTALLEGLEVD 60

SP-RING finger found in zinc finger MIZ domain-containing protein 2 (Zmiz2) and similar proteins; Zmiz2, also known as PIAS-like protein Zimp7 (zinc finger-containing, Miz1, PIAS-like protein on chromosome 7), is a novel PIAS-like protein that was initially identified as an androgen receptor (AR) interacting protein and functions as a transcriptional co-activator. It interacts with beta-catenin and enhances Wnt/beta-catenin-mediated transcription. It also associates with BRG1 and BAF57, components of the ATP-dependent mammalian SWI/SNF-like BAF chromatin-remodeling complexes, and thus plays a potential role in modulation of AR and/or other nuclear receptor-mediated transcription. For instance, it can increase the effects of BRG1 on AR-mediated transcriptional activity. Moreover, Zmiz2 physically interacts with PIAS proteins, especially PIAS3. Through this interaction, PIAS3 augments Zmiz2-mediated transcription, suggesting PIAS proteins may play a regulatory role in Zmiz-mediated transcription. Furthermore, Zmiz2 is involved in transcriptional regulation of factors essential for patterning in the dorsoventral axis. It is required for the restriction of the zebrafish organizer and mesoderm development. Zmiz2 contains a PAT domain, a highly conserved Siz/PIAS (protein inhibitor of activated signal transducer and activator of transcription) RING (SP-RING) finger, also known as msx-interacting zinc finger (Miz domain), and a strong intrinsic transactivation domain within the C-terminus. The SP-RING finger is a variant of RING finger, which lacks the second, fifth, and sixth zinc-binding residues of the consensus C3H2C3-/C3HC4-type RING fingers. It binds a single Zn ion, instead of two ions bound by typical RING fingers.

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gi 1907150329   2 CPLGKMRLTVPCRALTCAHLQSFDAALYLQMNEKKPTWTCPVCDKKAPYE 51
Cdd:cd16823    11 CPITFRRIQLPARGHDCRHIQCFDLESYLQLNCERGTWRCPVCNKTALLE 60

SP-RING finger found in Saccharomyces cerevisiae E3 SUMO-protein ligase SIZ1, SIZ2, and similar proteins; Saccharomyces cerevisiae SIZ proteins, also known as SAP and Miz-finger domain-containing proteins, are Siz/PIAS RING (SP-RING) family SUMO E3 ligases, and may be involved in a novel pathway of chromosome maintenance. They enhance SUMO modification with many substrates in vivo, but also exhibit unique substrate specificity. SIZ1, also known as ubiquitin-like protein ligase 1 (Ull1), modifies both cytoplasmic and nuclear proteins. It functions as an E3 factor specific for septin components. SIZ1-dependent substrates include Cdc3 and Cdc11 (septin subunits), Prp45 (a splicing factor), and the proliferating cell nuclear antigen (PCNA). SIZ2, also known as NFI1, interacts with Smt3, SUMO/Smt3 conjugating enzyme Ubc9, and a septin component Cdc3. Members of this subfamily contain an N-terminal SAP (scaffold attachment factor A/B (SAF-A/B), acinus and PIAS) box with the LXXLL signature, a PINT motif, a specific RING finger known as Siz/PIAS (protein inhibitor of activated signal transducer and activator of transcription) RING (SP-RING) finger, and an acidic C-terminal domain. The SP-RING finger is a variant of RING finger, which lacks the second, fifth, and sixth zinc-binding residues of the consensus C3H2C3-/C3HC4-type RING fingers. It binds a single Zn ion, instead of two ions bound by typical RING fingers.

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gi 1907150329   2 CPLGKMRLTVPCRALTCAHLQSFDAALYLQMNEKKPTWTCPVC 44
Cdd:cd16793     8 CPISYTRMKYPSKSINCKHLQCFDALWFLHSQLQIPTWQCPVC 50