SII-SWORD/CoKE huggingface dataset:
TRIM32, B-box type 1 zinc finger (TRIM32_Bbox1_Znf)
Type: Domain

TRIM32 (also known as 72 kDa Tat-interacting protein, or zinc finger protein HT2A, or BBS11) is an E3 ubiquitin-protein ligase that promotes degradation of several targets, including actin, PIASgamma, Abl interactor 2, dysbindin, X-linked inhibitor of apoptosis (XIAP), p73 transcription factor, among others . It plays important roles in neuronal differentiation of neural progenitor cells, as well as in controlling cell fate in skeletal muscle progenitor cells . It reduces PI3K-Akt-FoxO signalling in muscle atrophy by promoting plakoglobin-PI3K dissociation. It also functions as a pluripotency-reprogramming roadblock that facilitates cellular transition towards differentiation via modulating the levels of Oct4 and cMyc .

Moreover, TRIM32 is an intrinsic influenza A virus (IAV) restriction factor which senses and targets the polymerase basic protein 1 (PB1) for ubiquitination and protein degradation . It also plays a significant role in mediating the biological activity of the HIV-1 Tat protein in vivo, binding specifically to the activation domain of HIV-1 Tat ; it and can also interact with the HIV-2 and EIAV Tat proteins.

TRIM32 also regulates myoblast proliferation by controlling turnover of NDRG2 (N-myc downstream-regulated gene) and it negatively regulates tumour suppressor p53 to promote tumorigenesis . It also facilitates degradation of MYCN on spindle poles and induces asymmetric cell division in human neuroblastoma cells. In addition, TRIM32 plays important roles in regulation of hyperactivities and positively regulates the development of anxiety and depression disorders induced by chronic stress . It also plays a role in regeneration by affecting satellite cell cycle progression via modulation of the SUMO ligase PIASy (PIAS4). Defects in TRIM32 lead to limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and Bardet-Biedl syndrome .

TRIM32 belongs to the C-VII subclass of TRIM (tripartite motif)-NHL family that is defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a RING finger, Bbox1, and a coiled coil domain, as well as a NHL (named after proteins NCL-1, HT2A and Lin-41 that contain repeats folded into a six-bladed β-propeller) repeat domain positioned C-terminal to the RBCC domain.

This entry represents the type 1 B-box (Bbox1) zinc finger, which is characterised by a C6H2 zinc-binding consensus motif.
Zinc finger ZZ-type and EF-hand domain-containing protein 1, APC10/DOC1-like domain (ZZEF1_APC10)
Type: Domain

This group of proteins is found in animals and includes Zinc finger ZZ-type and EF-hand domain-containing protein 1 (ZZEF1). ZZEF1 is a histone H3 reader which may act as a transcriptional coactivator for KLF6 and KLF9 transcription factors .

This entry represents the APC10/DOC1-like domain of ZZEF1. It is homologous to the APC10 subunit/DOC1 domains present in E3 ubiquitin ligases (

), which mediate substrate ubiquitination (or ubiquitylation), and are components of the ubiquitin-26S proteasome pathway for selective proteolytic degradation.
Kalirin/Triple functional domain protein, SH3 domain 2 (Kalirin_TRIO_SH3_2)
Type: Domain

This entry includes a group of RhoGEFs, including Kalirin and Triple functional domain protein (TRIO) from mammals. Kalirin and TRIO are encoded by separate genes in mammals and by a single one in invertebrates. Kalirin and TRIO share the same complex multidomain structure and display several splice variants. They are implicated in secretory granule (SG) maturation and exocytosis . The longest Kalirin and TRIO proteins have a Sec14 domain, a stretch of spectrin repeats, a RhoGEF(DH)/PH cassette (also called GEF1), an SH3 domain, a second RhoGEF(DH)/PH cassette (also called GEF2), a second SH3 domain, Ig/FNIII domains, and a kinase domain. The first RhoGEF(DH)/PH cassette catalyses exchange on Rac1 and RhoG while the second RhoGEF(DH)/PH cassette is specific for RhoA. Kalirin and TRIO are closely related to p63RhoGEF and have PH domains of similar function. 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 .

TRIO contains a protein kinase domain and two guanine nucleotide exchange factor (GEF) domains . These functional domains suggest that it may play a role in signalling pathways controlling cell proliferation . TRIO may form a complex with LAR transmembrane protein tyrosine phosphatase (PT-Pase), which localises to the ends of focal adhesions and plays an important part in coordinating cell-matrix and cytoskeletal rearrangements necessary for cell migration . Its expression is associated with invasive tumour growth and rapid tumour cell proliferation in urinary bladder cancer .

Kalirin (

) promotes the exchange of GDP by GTP and stimulates the activity of specific Rho GTPases . There are several Kalirin isoforms in humans and mice. Each Kalirin isoform is composed of a unique collection of domains and may have different functions . In rat, isoforms 1 and 7 are necessary for neuronal development and axonal outgrowth, while isoform 6 is required for dendritic spine formation . In humans, the major isoform of Kalirin in the adult brain is Kalirin-7, which plays a critical role in spine formation/synaptic plasticity. Kalirin-7 has been linked to neuropsychiatric and neurological diseases such as Alzheimer's, Huntingtin's, ischemic stroke, schizophrenia, depression, and cocaine addiction .

This entry represents the second SH3 domain present in Kalirin and TRIO.
Kalirin/Triple functional domain protein, pleckstrin homology (PH) domain 1 (Kalirin_TRIO_PH_1)
Type: Domain

This entry represents the first pleckstrin homology (PH) domain present in Kalirin and TRIO.

This entry includes a group of RhoGEFs, including Kalirin and Triple functional domain protein (TRIO) from mammals. Kalirin and TRIO are encoded by separate genes in mammals and by a single one in invertebrates. Kalirin and TRIO share the same complex multidomain structure and display several splice variants. They are implicated in secretory granule (SG) maturation and exocytosis . The longest Kalirin and TRIO proteins have a Sec14 domain, a stretch of spectrin repeats, a RhoGEF(DH)/PH cassette (also called GEF1), an SH3 domain, a second RhoGEF(DH)/PH cassette (also called GEF2), a second SH3 domain, Ig/FNIII domains, and a kinase domain. The first RhoGEF(DH)/PH cassette catalyses exchange on Rac1 and RhoG while the second RhoGEF(DH)/PH cassette is specific for RhoA. Kalirin and TRIO are closely related to p63RhoGEF and have PH domains of similar function. 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 .

TRIO contains a protein kinase domain and two guanine nucleotide exchange factor (GEF) domains . These functional domains suggest that it may play a role in signalling pathways controlling cell proliferation . TRIO may form a complex with LAR transmembrane protein tyrosine phosphatase (PT-Pase), which localises to the ends of focal adhesions and plays an important part in coordinating cell-matrix and cytoskeletal rearrangements necessary for cell migration . Its expression is associated with invasive tumour growth and rapid tumour cell proliferation in urinary bladder cancer .

Kalirin (

) promotes the exchange of GDP by GTP and stimulates the activity of specific Rho GTPases . There are several Kalirin isoforms in humans and mice. Each Kalirin isoform is composed of a unique collection of domains and may have different functions . In rat, isoforms 1 and 7 are necessary for neuronal development and axonal outgrowth, while isoform 6 is required for dendritic spine formation . In humans, the major isoform of Kalirin in the adult brain is Kalirin-7, which plays a critical role in spine formation/synaptic plasticity. Kalirin-7 has been linked to neuropsychiatric and neurological diseases such as Alzheimer's, Huntingtin's, ischemic stroke, schizophrenia, depression, and cocaine addiction .
Motility protein A-like (MotA-like)
Type: Family

This family represents a group of bacterial proteins that are required for the rotation of the flagellar motor, which probably forms a transmembrane proton channel used to energize the flagellar rotary motor. This entry includes MotA and related proteins, such as PomA and LafT . These are integral membrane proteins that contains four transmembrane domains.
Whirlin, harmonin_N-like domain 1 (Whirlin_HN-like_dom1)
Type: Domain

Whirlin (also known as DFNB31) is a PDZ-scaffold protein that plays an indispensable role in the cochlea and retina. It is involved in vestibular and auditory hair cell transduction, and is also expressed by proprioceptive sensory neurons (pSNs) in dorsal root ganglia in mice . It has been shown to act as a cytoskeletal linker to ensure proper paranodal compaction and stabilization of the axonal cytoskeleton in myelinated axons .

Mutations in the whirlin gene cause retinal degeneration and hearing loss in Usher syndrome type II (USH2) and non-syndromic deafness, DFNB31 .

This entry represents the first harmonin_N-like domain of the long isoform of Whirlin, which is not present in the short isoform. It is thought to have a protein-binding role.
MerR transcriptional regulator (MerR_fam)
Type: Family

This entry represents the MerR family of transcriptional regulators, a group of transcriptional activators with similar N-terminal helix-turn-helix DNA binding regions and C-terminal effector binding regions that are specific to the effector recognised . MerR-type regulators are present in diverse bacterial genera in the cytoplasm. The helix-turn-helix DNA-binding motif is located in the N-terminal part of these transcriptional regulators and is followed by a coiled-coil region. The C-terminal part of merR-type regulators contains effector binding regions that are specific to the effector recognised. Most merR-type transcriptional regulators respond to environmental stimuli, like heavy metals, oxidative stress, or antibiotics and a subgroup of metalloregulators are bacterial transcription activators that respond to metal ions . This entry also represents MerR homologs such as YehV (now MlrA) .
Transcription intermediary factor 1-beta, B-box-type 2 zinc finger (TIF1b_Bbox2_Znf)
Type: Domain

TIF1-beta, also known as Kruppel-associated Box (KRAB)-associated protein 1 (KAP-1), belongs to the C-VI subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a plant homeodomain (PHD), and a bromodomain (Bromo) positioned C-terminal to the RBCC domain. It acts as a nuclear co-repressor that plays a role in transcription and in the DNA damage response .

Upon DNA damage, the phosphorylation of KAP-1 on serine 824 by the ataxia telangiectasia-mutated (ATM) kinase enhances cell survival and facilitates chromatin relaxation and heterochromatic DNA repair . It also regulates CHD3 nucleosome remodelling during the DNA double-strand break (DSB) response . Meanwhile, KAP-1 can be dephosphorylated by protein phosphatase PP4C in the DNA damage response . Moreover, KAP-1 is a co-activator of the orphan nuclear receptor NGFI-B (or Nur77) and is involved in NGFI-B-dependent transcription . It is also a coiled-coil binding partner, substrate and activator of the c-Fes protein tyrosine kinase . The N-terminal RBCC domains of TIF1-beta are responsible for the interaction with KRAB zinc finger proteins (KRAB-ZFPs), MDM2, MM1, C/EBPbeta, and the regulation of homo- and heterodimerization . The C-terminal PHD/Bromo domains are involved in interacting with SETDB1, Mi-2alpha and other proteins to form complexes with histone deacetylase or methyltransferase activity .

This entry represents the B-box-type 2 zinc finger from TIF1-beta, characterised by a CHC3H2 zinc-binding consensus motif.
Transcription intermediary factor 1-beta, B-box-type 1 zinc finger (TIF1b_Bbox1_Znf)
Type: Domain

This entry represents the B-box-type 1 zinc finger from TIF1-beta, which is characterised by a C6H2 zinc-binding consensus motif.

TIF1-beta, also known as Kruppel-associated Box (KRAB)-associated protein 1 (KAP-1), belongs to the C-VI subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a plant homeodomain (PHD), and a bromodomain (Bromo) positioned C-terminal to the RBCC domain. It acts as a nuclear co-repressor that plays a role in transcription and in the DNA damage response .

Upon DNA damage, the phosphorylation of KAP-1 on serine 824 by the ataxia telangiectasia-mutated (ATM) kinase enhances cell survival and facilitates chromatin relaxation and heterochromatic DNA repair . It also regulates CHD3 nucleosome remodelling during the DNA double-strand break (DSB) response . Meanwhile, KAP-1 can be dephosphorylated by protein phosphatase PP4C in the DNA damage response . Moreover, KAP-1 is a co-activator of the orphan nuclear receptor NGFI-B (or Nur77) and is involved in NGFI-B-dependent transcription . It is also a coiled-coil binding partner, substrate and activator of the c-Fes protein tyrosine kinase . The N-terminal RBCC domains of TIF1-beta are responsible for the interaction with KRAB zinc finger proteins (KRAB-ZFPs), MDM2, MM1, C/EBPbeta, and the regulation of homo- and heterodimerization . The C-terminal PHD/Bromo domains are involved in interacting with SETDB1, Mi-2alpha and other proteins to form complexes with histone deacetylase or methyltransferase activity .
Kelch-like protein 7, BACK domain (KLHL7_BACK)
Type: Domain

The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding , while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins . In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins . Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases .

Kelch-like protein 7 (KLHL7) belongs to the KLHL family . It serves as a substrate-specific adapter in the Cul3-dependent ubiquitin ligase complex and is linked to autosomal dominant retinitis pigmentosa (adRP) . This entry represents the BACK domain.
Ubiquitin-specific peptidase 24, ubiquitin-like domain (UBP24_Ubl)
Type: Domain

Ubiquitin-specific peptidase 24 (USP24, MEROPS identifier C19.047) is a de-ubiquitinating enzyme that is associated with late-onset Parkinson's Disease . The enzyme is known to remove ubiquitin from damage-specific DNA-binding protein 2 (DDB2), increasing its stability. DDB2 is involved in DNA damage recognition in the nucleotide excision repair pathway, and is a component of an E3 ligase that targets XPC, histones and DDB2 itself . USP24 also de-ubiquitinates p53, and cells are resistant to apoptosis following UV irradiation if USP24 is depleted because p53 is stabilized . Single-nucleotide polymorphisms of the USP24 gene have been identified in lung cancer malignancy and could be diagnostic markers for the disease . The USP24 gene is up-regulated when the USP9X gene is down-regulated by shRNA, leading to increased survival of B-cell myeloma cells . USP24 positively regulates ferritinophagy, a process in which ferritin is degraded in lysosomes and releases free iron .

This entry represents the ubiquitin-like (Ubl) domain of UBP24.
Kelch repeat and BTB domain-containing protein 3, BACK domain (KBTBD3_BACK)
Type: Domain

The BTB superfamily includes KLHL (Kelch-like), KBTBD (Kelch repeat and BTB domain-containing), and KLHDC (Kelch domain-containing) subfamilies, which encompass structurally related molecules that differ in the types and numbers of their protein domains. The domain composition can appear to vary depending on the protein domain prediction program. For example, KLHL29, KLHL31, KLHL40, and KLHL41 were previously assigned within the KBTBD family as KBTBD9, KBTBD1, KBTBD5, and KBTBD10 respectively. KBTBD proteins have typically one BTB/POZ domain, occasionally a BACK domain, and two to four Kelch motifs .

KBTBD3, also termed BTB and kelch domain-containing protein 3 (BKLHD3), is a BTB-Kelch family protein. Its function remains unclear. This entry represents the BACK domain .
Probable E3 ubiquitin-protein ligase MID2, B-box-type 2 zinc finger (MID2_Bbox2_Zfn)
Type: Domain

This entry represents the B-box-type 2 zinc finger of MID2, which is characterised by a CHC3H2 zinc-binding consensus motif.

MID2 shares high structural and functional similarities with MID1, an ubiquitin E3 ligase that regulates the turnover of microtubular protein phosphatase 2Ac. MID2 interacts with Astrin (a microtubule-organizing protein) and regulates Astrin levels to promote cell division . MID1 and MID2 may play roles in regulating tissue remodelling in early development .

Mutations in the MID2 gene lead to human X-linked intellectual disability (XLID) .
Probable E3 ubiquitin-protein ligase MID2, B-box-type 1 zinc finger (MID2_Bbox1_Zfn)
Type: Domain

MID2 shares high structural and functional similarities with MID1, an ubiquitin E3 ligase that regulates the turnover of microtubular protein phosphatase 2Ac. MID2 interacts with Astrin (a microtubule-organizing protein) and regulates Astrin levels to promote cell division . MID1 and MID2 may play roles in regulating tissue remodelling in early development .

Mutations in the MID2 gene lead to human X-linked intellectual disability (XLID) .

This entry represents the B-box-type 1 zinc finger of MID2, which is characterised by a C6H2 zinc-binding consensus motif.
E3 ubiquitin-protein ligase Trim36, B-box-type 2 zinc finger (TRIM36_Bbox2_Zfn)
Type: Domain

The tripartite motif-containing protein (Trim) family is defined by the presence of a common domain structure composed of a RING finger, a B-box, and a coiled-coil motif . Trim36 is a E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. It interacts with centromere protein-H, one of the kinetochore proteins and is involved in chromosome segregation and cell cycle regulation. This protein has been associated with anencephaly . It may play a role in the acrosome reaction and fertilisation .

This entry represents the B-box-type 2 zinc finger of Trim36, which is characterised by a CHC3H2 zinc-binding consensus motif.
E3 ubiquitin-protein ligase Trim36, B-box-type 1 zinc finger (TRIM36_Bbox1_Zfn)
Type: Domain

This entry represents the B-box-type 1 zinc finger of Trim36, which is characterised by a C6H2 zinc-binding consensus motif.

The tripartite motif-containing protein (Trim) family is defined by the presence of a common domain structure composed of a RING finger, a B-box, and a coiled-coil motif . Trim36 is a E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. It interacts with centromere protein-H, one of the kinetochore proteins and is involved in chromosome segregation and cell cycle regulation. This protein has been associated with anencephaly . It may play a role in the acrosome reaction and fertilisation .
Actin-binding protein IPP, BACK domain (IPP_BACK)
Type: Domain

IPP (also known as Kelch-like protein 27) belongs to the KLHL family. It binds to actin through its kelch repeat domain . It may play a role in organizing the actin cytoskeleton, however, its exact function is not clear. This entry represents the BACK domain.
Kelch-like protein 23, BACK domain (KLHL23_BACK)
Type: Domain

The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding , while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins . In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins . Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases .

Kelch-like protein 23 (KLHL23) belongs to the KLHL family . KLHL23 overexpression is associated with increased cell proliferation and invasion in gastric cancer. Downregulation of KLHL23 is associated with invasion, metastasis, and poor prognosis of hepatocellular carcinoma and pancreatic cancer . This entry represents the BACK domain.
Kelch-like protein 21, BACK domain (KLHL21_BACK)
Type: Domain

The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding , while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins . In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins . Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases .

Kelch-like protein 21 (KLHL21) is a substrate adaptor protein in the Cul3-KLHL21 E3 ubiquitin ligase complex required for efficient chromosome alignment and cytokinesis. During cytokinesis, it localises to midzone microtubules in anaphase and recruits aurora B and Cul3 to this region . KLHL21 also targets IkappaB kinase-beta to regulate nuclear factor kappa-light chain enhancer of activated B cells (NF-kappaB) signalling negatively . This entry represents the BACK domain.