SII-SWORD/CoKE huggingface dataset:
Sorting nexin-17, FERM domain, N-terminal subdomain (SNX17_FERM_N)
Type: Domain

SNX17 contains a PX (Phox homology) domain and a FERM (Band 4.1, ezrin, radixin, moesin) domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

Sorting nexin-17 (SNX17) belongs to the sorting nexin family, which contains a conserved PX (phox homology) domain that may be responsible for binding to specific phosphoinositides . SNX17 is a critical regulator of endosomal recycling of numerous receptors, channels, and other transmembrane proteins . It binds to Asn-Pro-Xaa-Tyr (NPxY) sequences in the cytoplasmic tails of cargo such as LDL receptors and the amyloid precursor protein . SNX17 also affects T cell activation by regulating T cell receptor and integrin recycling .
Syntaxin-2, SNARE motif (STX2_SNARE)
Type: Domain

Syntaxin-2 (STX2), also known as epimorphin, belongs to the syntaxin family, which is a group of the membrane integrated proteins participating in exocytosis. Syntaxins are associated with various intracellular membrane compartments and have been implicated in various physiological processes such as axonal growth and cell division .

STX2 is essential for epithelial morphogenesis . It may mediate Ca2+-regulation of exocytosis acrosomal reaction in sperm .

This entry represents the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) motif of STX2, which consist of coiled-coil helices.
Syntaxin-17, SNARE motif (STX17_SNARE)
Type: Domain

Syntaxin-17 (STX17) belongs to the syntaxin family, which is a group of the membrane integrated proteins participating in exocytosis. Syntaxins are associated with various intracellular membrane compartments and have been implicated in various physiological processes such as axonal growth, cell division and autophagosome-lysosome fusion .

STX17 is required to maintain the architecture of ER-Golgi intermediate compartment and Golgi . STX17 is also involved in the fusion of autophagosomes with endosomes/lysosomes. Its unique C-terminal hairpin structure mediated by two tandem transmembrane domains is essential for its association with the autophagosomal membrane .

This entry represents the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) motif of STX17, which consist of coiled-coil helices.
Synaptotagmin-13, C2B domain (Syt13_C2B)
Type: Domain

Synaptotagmin-13 (Syt13), a member of class 6 synaptotagmins, belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains (also known as C2A and C2B domains). Most of the synaptotagmins have a unique N-terminal domain (transmembrane region) that is involved in membrane anchoring or specific ligand binding. Unlike most of the synaptotagmins, SYT13 does not have an N-terminal transmembrane region. Its C2 domains are lacking almost all the residues involved in Ca2+ binding . It is highly expressed in brain and also detectable at lower levels in non-neuronal tissues . SYT13 can suppress liver tumour cells and this function may be mediated through pathways implicated in mesenchymal to epithelial transition . It also affects insulin secretion .
Rabphilin-3A, FYVE domain (FYVE_RPH3A)
Type: Domain

In humans, Rabphilin-3A (RPH3A) is an effector protein that binds to the GTP-bound form of Rab3A, which is one of the most abundant Rab proteins in neurons and predominantly localized to synaptic vesicles. It contains an N-terminal Rab3A effector domain (RabBD (Rab-binding) domain), a proline-rich linker region, and two tandem C2 domains . The effector domain binds specifically to the activated GTP-bound state of Rab3A and harbors a conserved FYVE zinc finger. The C2 domains are responsible for the binding of phosphatidylinositol-4,5-bisphosphate (PIP2) , a key player in the neurotransmitter release process . RPH3A may interact with the SNARE complex and regulate synaptic vesicle exocytosis and Ca2+-triggered neurotransmitter release . It has been linked to neurodegenerative diseases, such as Huntington's disease , Lewy body disease and Alzheimer's disease .

This entry represents the FYVE domain of Rabphilin-3A, which resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif.
Chromodomain-helicase-DNA-binding protein 5, DEAH-box helicase domain (DEXHc_CHD5)
Type: Domain

There are nine members of the Chromodomain, Helicase, DNA-binding (CHD) family. They are characterised by two chromodomains arranged in tandem, N-terminal to the ATPase/helicase domain. Chromodomains are comprised of a β-sheet folded against an α-helix that collectively mediates binding to methyl-lysine residues .

Chromodomain-helicase-DNA-binding protein 5 (CHD5) is a chromatin-remodeling protein that binds DNA through histones and regulates gene transcription. It is thought to specifically recognize and bind trimethylated 'Lys-27' (H3K27me3) and non-methylated 'Lys-4' of histone H3 and plays a role in the development of the nervous system by activating the expression of genes promoting neuron terminal differentiation . In parallel, it may also positively regulate the trimethylation of histone H3 at 'Lys-27' thereby specifically repressing genes that promote the differentiation into non-neuronal cell lineages. As a tumor suppressor, it regulates the expression of genes involved in cell proliferation and differentiation . CHD5 is almost exclusively expressed in brain and testis. It probably regulates histone hyperacetylation and the replacement of histones by transition proteins in chromatin, being required for spermatogenesis and chromatin condensation . CHD5 plays a role in the development of the nervous system .
Sperm-associated antigen 5 (Astrin)
Type: Family

Sperm-associated antigen 5 (Spag5, also known as astrin) is an essential component of the mitotic spindle required for normal chromosome segregation and progression into anaphase . It is part of the astrin (SPAG5)-kinastrin (SKAP) complex that promotes stable microtubule-kinetochore attachments . Targeting Astrin to the centrosome during the S and G2 phases requires another protein, Ninein . Postmitotically, astrin interacts with USH proteins and may function together in microtubule-based cytoplasmic trafficking of proteins that are essential for cilium formation, maintenance and/or function .
Zinc finger FYVE domain-containing protein 26 (ZFYVE26)
Type: Family

Zinc finger FYVE domain-containing protein 26 (ZFYVE26, also known as SPG15) is a phosphatidylinositol 3-phosphate-binding protein recruited to the midbody during cytokinesis and required for the abcission step in cytokinesis (cleaving of the midbody in two) . It may also be required for efficient homologous recombination DNA double-strand break repair .

Mutations in ZFYVE26 cause spastic paraplegia 15, autosomal recessive (SPG15), which is a form of spastic paraplegia, a neurodegenerative disorder characterised by a slow, gradual, progressive weakness and spasticity of the lower limbs .
LIM domain and actin-binding protein 1, Lim domain (EPLIN_Lim_dom)
Type: Domain

LIM domain and actin-binding protein 1 (LIMA1, also know as EPLIN) is a cytoskeleton-associated protein that regulates actin dynamics by cross-linking and stabilising filaments . It is a tumour suppressor whose expression inversely correlates with cell growth, motility, invasion and cancer mortality. It interacts and stabilizes F-actin filaments and stress fibers, which correlates with its ability to suppress anchorage independent growth . EPLIN was first identified as the product of a gene that is transcriptionally down-regulated or lost in a number of human epithelial tumour cells . In humans, there are two EPLIN isoforms, EPLIN alpha and EPLIN beta, both have a centrally located LIM domain that may mediate self-dimerisation. EPLIN inhibits Arp2/3 complex-mediated branching nucleation of actin filaments and stabilises actin filament networks . EPLIN can be regulated through phophoryltion by extracellular signal-regulated kinase (ERK) .

This entry represents the Lim domain of EPLIN, which function as an adaptor or scaffold to support the assembly of multimeric protein. This domain shows two characteristic zinc finger motifs. The two zinc fingers contain eight conserved residues, mostly cysteines and histidines, which coordinately bond to two zinc atoms .
Cation channel sperm-associated protein 4 (CatSper4)
Type: Family

CATSPER (cationic channel of sperm) is a complex ion channel that mediates Ca2+ entry in sperm flagellum and is required for sperm hyperactivation and male fertility . The CATSPER channel consists of four CatSper proteins (CatSper1-4) that form a tetramer surrounding a Ca(2+)-selective pore. In addition to the pore-forming proteins, the CATSPER channel contains auxiliary subunits .

All four CatSper proteins are predicted to contain a common coiled-coil protein-protein interaction domain in their C-terminal tail and all four are required for male fertility and sperm cell hyperactivated motility . The CatSper channel of human sperm is activated by progesterone .

This entry represents cation channel sperm-associated protein 4 (CatSper4) .
A-kinase anchor protein 9/Pericentrin (AKAP9/Pericentrin)
Type: Family

A-kinase anchor protein 9 (AKAP9, also known as AKAP 350) and pericentrin (pericentrin-B, kendrin) are large coiled-coil proteins found in mammalian centrosomes that serve to recruit structural and regulatory components including dynein and protein kinase . These scaffold proteins contain a pericentrin-AKAP-450 centrosomal targeting (PACT) domain .

Mutations of AKAP9 cause long QT syndrome 11 (LQT11), which is a heart disorder characterised by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias . AKAP9 has also been implicated in breast cancer and sporadic papillary thyroid carcinomas . In mice, AKAP9 is essential for Spermatogenesis and sertoli cell maturation .
Cation channel sperm-associated protein 1 (CatSper1)
Type: Family

CATSPER (cationic channel of sperm) is a complex ion channel that mediates Ca2+ entry in sperm flagellum and is required for sperm hyperactivation and male fertility . The CATSPER channel consists of four CatSper proteins (CatSper1-4) that form a tetramer surrounding a Ca(2+)-selective pore. In addition to the pore-forming proteins, the CATSPER channel contains auxiliary subunits .

All four CatSper proteins are predicted to contain a common coiled-coil protein-protein interaction domain in their C-terminal tail and all four are required for male fertility and sperm cell hyperactivated motility . The CatSper channel of human sperm is activated by progesterone .

This entry represents cation channel sperm-associated protein 1 (CatSper1) .
Cation channel sperm-associated protein 2 (CatSper2)
Type: Family

CATSPER (cationic channel of sperm) is a complex ion channel that mediates Ca2+ entry in sperm flagellum and is required for sperm hyperactivation and male fertility . The CATSPER channel consists of four CatSper proteins (CatSper1-4) that form a tetramer surrounding a Ca(2+)-selective pore. In addition to the pore-forming proteins, the CATSPER channel contains auxiliary subunits .

All four CatSper proteins are predicted to contain a common coiled-coil protein-protein interaction domain in their C-terminal tail and all four are required for male fertility and sperm cell hyperactivated motility . The CatSper channel of human sperm is activated by progesterone .

This entry represents cation channel sperm-associated protein 2 (CatSper2) .
Cation channel sperm-associated auxiliary subunit beta (CATSPERB)
Type: Family

CatSper (cationic channel of sperm) is a complex ion channel that mediates Ca2+ entry in sperm flagellum and is required for sperm hyperactivation and male fertility . The CATSPER channel consists of four CatSper proteins (CatSper1-4) that form a tetramer surrounding a Ca(2+)-selective pore.

In addition to the pore-forming proteins, the CATSPER channel contains auxiliary subunits, beta, gamma, delta and epsilon (CATSPERB/G/D/E) , CATSPERB is included in this entry, which mediates extensive contacts with other subunits and thus, it is involved in stabilising the channel complex.
Centrosome-associated protein 350/Coiled-coil domain-containing protein 187 (CEP350/CC187)
Type: Family

Centrosome-associated protein 350 (CEP350 or CAP350) plays an essential role in centriole growth by stabilising a procentriolar seed composed of, at least, SASS6 and CENPJ . It is required for anchoring microtubules to the centrosomes and for the integrity of the microtubule network . It also stabilises Golgi-associated microtubules and maintains a continuous pericentrosomal Golgi ribbon .
CEP350 possesses a CAP-Gly domain which is targeted to the centrosome or the Golgi-like network and binds microtubules through an N-terminal basic region .

This family also includes the coiled-coil domain-containing protein 187 (CC187), a centrosomal protein whose function is still unknown.
Cation channel sperm-associated auxiliary subunit delta/epsilon (CATSPERD/E)
Type: Family

CATSPER (cationic channel of sperm) is a complex ion channel that mediates Ca2+ entry in sperm flagellum and is required for sperm hyperactivation and male fertility . The CATSPER channel consists of four CatSper proteins (CatSper1-4) that form a tetramer surrounding a Ca(2+)-selective pore. In addition to the pore-forming proteins, the CATSPER channel contains auxiliary subunits, including CatSperD (cation channel sperm-associated protein subunit delta) and CatSperE. CatSperD is essential for the cation channel function and may play a role in channel assembly or transport.
Serine/threonine-protein kinase PAK5, catalytic domain (STKc_PAK5)
Type: Domain

Serine/threonine-protein kinase PAK 5 (PAK5, also known as PAK7) belongs to the mammalian p21-activated kinase (PAK) family of serine/threonine kinases that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, proliferation or cell survival .
Kelch repeat and BTB domain-containing protein 8, BTB/POZ domain (BTB/POZ_KBTBD8)
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 .

Kelch repeat and BTB domain-containing protein 8 (KBTBD8) belongs to the BTB-kelch protein family. KBTBD8 localises in the Golgi apparatus and translocates to the spindle apparatus during mitosis . It acts as a substrate-specific adaptor of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of neural crest specification. The BCR(KBTBD8) complex monoubiquitylates NOLC1 and its paralog TCOF1, the mutation of which underlies the neurocristopathy Treacher Collins syndrome . This entry represents the BTB/POZ domain.
IQ calmodulin-binding motif-containing protein 1 (IQCB1)
Type: Family

IQ calmodulin-binding motif-containing protein 1 (IQCB1, also called NPHP5) is involved in ciliogenesis . Mutations in IQCB1 gene cause Senior-Loken syndrome 5 (SLSN5), which is a renal-retinal disorder characterised by progressive wasting of the filtering unit of the kidney (nephronophthisis), with or without medullary cystic renal disease, and progressive eye disease .
Arf GTPase activating protein 3, BAR domain (BAR_ASAP3)
Type: Domain

The Arf GAPs (GTPase-activating proteins) are a family of multidomain proteins with the common function of accelerating the hydrolysis of GTP bound to Arf proteins. ASAP proteins are a subtype of Arf GAPs. ASAP3 (Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 3, also known as ACAP4, DDEFL1 (Development and Differentiation Enhancing Factor-Like 1), or centaurin beta-6), is a focal adhesion-associated Arf GAP that functions in cell migration and invasion of cancers . It is an Arf6-specific GTPase activating protein (GAP) and is co-localized with Arf6 in ruffling membranes upon EGF stimulation . ASAP3 promotes cell proliferation , being implicated in the pathogenesis of hepatocellular carcinoma and plays a role in regulating cell migration and invasion .

ASAP3 (Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 3) contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain and ankyrin (ANK) repeats. Unlike ASAP1 and ASAP2, ASAP3 do not have an SH3 domain at the C-terminal.

This entry represents the N-terminal BAR domain, domains that form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions [

,

,

. The BAR domain of the related protein ASAP1 mediates membrane bending, is essential for function, and auto inhibits GAP activity by interacting with the PH and/or Arf GAP domains.
PRKAA2, UBA-like autoinhibitory domain (PRKAA2)
Type: Domain

5'-AMP-activated protein kinase catalytic subunit alpha (PRKAA) is the catalytic subunit of the AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism . There are two AMPK alpha-subunit isoforms in mammals: PRKAA1 and PRKAA2. They have an N-terminal Ser/Thr kinase domain followed by an ubiquitin-associated (UBA)-like AID and a C-terminal AMPK regulatory domain .

This entry represents the AID that is responsible for PRKAA autoinhibition. PRKAA2 has been associated with type 2 diabetes .
BBSome complex member BBS1 (BBS1)
Type: Family

Bardet-Biedl syndrome is characterised by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation . Bardet-Biedl syndrome proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10) form the BBSome complex, which functions as a coat complex required for sorting of specific membrane proteins to the primary cilia . The ciliary trafficking function of BBSome is regulated by LZTFL1 (Leucine-zipper transcription factor-like 1) .

Primary cilia are ubiquitous cellular appendages that provide important sensory and signalling functions and their dysfunction underlies numerous human genetic disorders. The proteins disrupted in the human ciliary disorder Bardet-Biedl syndrome (BBS) are required for the localisation of G protein-coupled receptors to primary cilia on central neurons. The alteration of signalling caused by mislocalisation of ciliary signalling proteins underlies the BBS phenotype . Of the 12 known BBS genes, BBS1 is the most commonly mutated .

This entry includes BBS1, is the most important BBSome subunit for cargo recognition as it mediates the interaction of the GTP-bound Arf-like GTPase ARL6 with the BBSome, a critical step in the recruitment of the BBSome to membranes .
Cyclin-dependent kinase 6 (CDK6)
Type: Family

Cyclin-dependent kinase 6 (CDK6) is a D-Cyclin-activated kinase that is involved in driving the cell cycle through inactivation of pRB in G1 phase . It has been implicated in cell proliferation and tumor angiogenesis . It is also involved in cell differentiation through regulation of gene expression . CDK6 interacts with the p65 subunit of NFkB in the nucleus, and is found at promoters of many transcriptionally active NFkB target genes .
Baculoviral IAP repeat-containing protein 1 (Naip)
Type: Family

Baculoviral IAP repeat-containing protein 1 or neuronal apoptosis inhibitory protein (NAIP) is an anti-apoptotic protein which acts by inhibiting the activities of CASP3, CASP7 and CASP9. NAIP contains three baculoviral IAP repeat (BIR) domains at the amino-terminal region and a ATP/GTP binding site . NAIP has been shown to inhibit apoptosis in neurons and in several mammalian cell lines .
Molecular chaperone MKKS (MKKS)
Type: Family

Molecular chaperone MKKS (also known as BBS6) is a chaperonin-like protein that is involved in folding newly synthesised polypeptides . As part of the BBS/CCT complex mediates BBSome assembly, which is involved in regulating ciliogenesis and transport of vesicles to the cilia . During mitosis, MKKS localises throughout the pericentriolar material (PCM) and the intercellular bridge. It is required for cytokinesis . It may play a role in protein processing in limb, cardiac and reproductive system development .

Mutations in MKKS gene cause McKusick-Kaufman syndrome (MKKS), which is autosomal recessive developmental disorder . Mutations in MKKS gene also cause Bardet-Biedl syndrome 6 (BBS6), which is characterised by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation .
Tetratricopeptide repeat protein 8 (BBS8)
Type: Family

Tetratricopeptide repeat protein 8 (TTC8, also known as BBS8) is part of the BBSome complex (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10), which is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia . The ciliary trafficking function of the BBSome is regulated by LZTFL1 (Leucine-zipper transcription factor-like 1) .

Primary cilia are ubiquitous cellular appendages that provide important sensory and signalling functions and their dysfunction underlies numerous human genetic disorders. The proteins disrupted in the human ciliary disorder Bardet-Biedl syndrome (BBS) are required for the localisation of G protein-coupled receptors to primary cilia on central neurons. The alteration of signalling caused by mislocalisation of ciliary signalling proteins underlies the BBS phenotype . BBS8 is one of the genes involved in BBS. A splice-site mutation in TTC8/BBS8 is also known to cause nonsyndromic retinitis pigmentosa (RP) .
PRKAA1, UBA-like autoinhibitory domain (PRKAA1_UBA)
Type: Domain

5'-AMP-activated protein kinase catalytic subunit alpha (PRKAA or AMPKalpha) is the catalytic subunit of the AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism . There are two AMPK alpha-subunit isoforms in mammals: PRKAA1 and PRKAA2. They have an N-terminal Ser/Thr kinase domain followed by an ubiquitin-associated (UBA)-like AID and a C-terminal AMPK regulatory domain .

This entry represents the AID that is responsible for PRKAA autoinhibition.
Two pore channel protein 2 (TPC2)
Type: Family

This entry represents TPC2. It modulates neural differentiation of mouse embryonic stem cells . It may also be involved in smooth muscle contraction .

Two-pore segment channels (TPCs or TPCNs) are located in membranes of acidic intracellular organelles (such as endo-lysosomes and plant vacuoles) and contain two putative pore-forming repeats. Each of these repeats contains six transmembrane segments and an intervening pore-loop, an architecture featured in voltage-gated channels . Functional TPC channels are assembled from two TPC protein subunits forming a pore that conducts mainly Ca2 and Na. TPCs exist as three isoforms (TPC1-3): TPC1 and TPC2 are the most universal isoforms since TPC3 is absent from the genomes of many animals including those of human, mice, rats and flies .