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0ITSN1_HUMAN*   SwissProt (?) | Description Local Annotation Link Reference
General Information
DescriptionIntersectin-1 (sh3 domain-containing protein 1a) (sh3p17).
SpeciesHomo sapiens (NCBI taxonomy ID: 9606)
GO0005509 calcium ion binding (NAS)
0005085 guanyl-nucleotide exchange factor activity (NAS)
0005515 protein binding (IPI)
0048488 synaptic vesicle endocytosis (TAS)

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schematic display of those terms with internal associations, click the node and browse the corresponding GO term
Domain Architecture (Details)
InterPro domains unassigned to SynO:
The EH (for Eps15 Homology) domain is a protein-protein interaction module of approximately 95 residues which was originally identified as a repeated sequence present in three copies at the N-terminus of the tyrosine kinase substrates Eps15 and Eps15R . The EH domain was subsequently found in several proteins implicated in endocytosis.esicle transport and signal transduction in organisms ranging from yeast to mammals. EH domains are present in one to three copies and they may include calcium-binding domains of the EF-hand type . Eps15 is divided into three domains: domain I contains signatures of a regulatory domain.ncluding a candidate tyrosine phosphorylation site and EF-hand-type calcium-binding domains.omain II presents the characteristic heptad repeats of coiled-coil rod-like proteins.nd domain III displays a repeated aspartic acid-proline-phenylalanine motif similar to a consensus sequence of several methylases .EH domains have been shown to bind specifically but with moderate affinity to peptides containing short.nmodified motifs through predominantly hydrophobic interactions. The target motifs are divided into three classes: class I consists of the concensus Asn-Pro-Phe (NPF) sequence; class II consists of aromatic and hydrophobic di- and tripeptide motifs.ncluding the Phe-Trp (FW).rp-Trp (WW).nd Ser-Trp-Gly (SWG) motifs; and class III contains the His-(Thr/Ser)-Phe motif (HTF/HSF) . The structure of several EH domains has been solved by NMR spectroscopy. The fold consists of two helix-loop-helix characteristic of EF-hand domains.onnected by a short antiparallel beta-sheet. The target peptide is bound in a hydrophobic pocket between two alpha helices. Sequence analysis and structural data indicate that not all the EF-hands are capable of binding calcium because of substitutions of the calcium-liganding residues in the loop . This domain is often implicated in the regulation of protein transport/sorting and membrane trafficking. Messenger RNA translation initiation and cytoplasmic poly(A) tail shortening require the poly(A)-binding protein (PAB) in yeast. The PAB-dependent poly(A) ribonuclease (PAN) is organised into distinct domains containing repeated sequence elements .
  IPR000261:EPS15 homology (EH)
This domain consists of a duplication of two EF-hand each unit is composed of two helices connected by a twelve-residue calcium-binding loop. The calcium ion in the EF-hand loop is coordinated in a pentagonal bipyramidal configuration. Many calcium-binding proteins contain an EF-hand type calcium-binding domain . These include: calbindin D9K.100 proteins such as calcyclin.olcalcin phl p 7 (a calcium-binding pollen allergen).steonectin.arvalbumin.almodulin family of proteins (troponin C.altractin.dc4p.yosin essential chain.alcineurin.ecoverin.eurocalcin).lasmodial-specific CaII-binding protein Cbp40.enta-EF-Hand proteins (sorcin.rancalcin.alpain).s well as multidomain proteins such as phosphoinositide-specific phospholipase C.ystrophin.b1 and alpha-actinin. The fold consists of four helices and an open array of two hairpins.
  IPR011992:EF-Hand type
The C2 domain is a Ca2+-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes.ncluding phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies ofthe C1 domain in Protein Kinase C (that bind phorbol esters and diacylglycerol) (see )and the protein kinase catalytic domain (see ). Regions withsignificant homology to the C2-domain have been found in many proteins.The C2 domain is thought to be involved in calcium-dependent phospholipidbinding and in membrane targetting processes such as subcellular localisation. The 3D structure of theC2 domain of synaptotagmin has been reported.he domain forms an eight-stranded beta sandwich constructed around a conserved 4-stranded motif.esignated a C2 key . Calcium binds ina cup-shaped depression formed by the N- and C-terminal loops of theC2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca2+-binding loops are located at the end of an 8 stranded antiparallel beta sandwich.
  IPR000008:C2 calcium-dependent membrane targeting
The pleckstrin homology (PH) domain is a domain of about 100 residues that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton .The function of this domain is not clear.everal putative functions have been suggested:binding to the beta/gamma subunit of heterotrimeric G proteins.inding to lipids..g. phosphatidylinositol-4.-bisphosphate.inding to phosphorylated Ser/Thr residues.ttachment to membranes by an unknown mechanism.It is possible that different PH domains have totally different ligand requirements.The 3D structure of several PH domains has been determined . All known cases have a common structure consisting of two perpendicular anti-parallel beta sheets.ollowed by a C-terminal amphipathic helix. The loops connecting the beta-strands differ greatly in length.aking the PH domain relatively difficult to detect. There are no totally invariant residues within the PH domain.Proteins reported to contain one more PH domains belong to the following families:Pleckstrin.he protein where this domain was first detected.s the major substrate of protein kinase C in platelets. Pleckstrin is one of the rare proteins to contains two PH domains.Ser/Thr protein kinases such as the Akt/Rac family.he beta-adrenergic receptor kinases.he mu isoform of PKC and the trypanosomal NrkA family.Tyrosine protein kinases belonging to the Btk/Itk/Tec subfamily.Insulin Receptor Substrate 1 (IRS-1).Regulators of small G-proteins like guanine nucleotide releasing factor GNRP (Ras-GRF) (which contains 2 PH domains).uanine nucleotide exchange proteins like and Saccharomyces cerevisiae CDC24.TPase activating proteins like rasGAP and BEM2/IPL2.nd the human break point cluster protein bcr.Cytoskeletal proteins such as dynamin (see ).aenorhabditis elegans kinesin-like protein unc-104 (see ).pectrin beta-chain.yntrophin (2 PH domains) and S. cerevisiae nuclear migration protein NUM1.Mammalian phosphatidylinositol-specific phospholipase C (PI-PLC) (see ) isoforms gamma and delta. Isoform gamma contains two PH domains.he second one is split into two parts separated by about 400 residues.Oxysterol binding proteins OSBP.. cerevisiae OSH1 and YHR073w.Mouse protein citron. putative rho/rac effector that binds to the GTP-bound forms of rho and rac.Several S. cerevisiae proteins involved in cell cycle regulation and bud formation like BEM2.EM3.UD4 and the BEM1-binding proteins BOI2 (BEB1) and BOI1 (BOB1).C. elegans protein MIG-10.C. elegans hypothetical proteins C04D8.1.06H7.4 and ZK632.12.S. cerevisiae hypothetical proteins YBR129c and YHR155w.
Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand. This type of domain consists of a twelve residue loop flanked on both side by a twelve residue alpha-helical domain. In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1.... and 12; these residues are denoted by X...Y.X and -Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand).
  IPR002048:Calcium-binding EF-hand
Phagocytes form the first line of defence against invasion by micro-organisms. Engulfing of bacteria by neutrophils is accompanied by theconsumption of large amounts of oxygen - a so-called respiratory burst.Defects in phagocytosis involving the lack of a respiratory burst giverise to chronic granulomatous disease (CGD).n which patients are pre-disposed to infection.ften from otherwise non-pathogenic bacteria .Regulation of the respiratory burst takes place at the phagocytic vacuole.The process is mediated by NADPH oxidase.hich transports electrons acrossthe plasma membrane to form superoxide (an oxygen molecule with an extraelectron that is toxic to normal cells) in the vacuole interior. Theelectrons are carried across the membrane by a short electron transportchain in the form of an unusual flavocytochrome b .To conserve NADPH and avoid the toxic effects of superoxide.he oxidase remains inactive until it receives an appropriate stimulus. Activationinvolves the participation of a number of cytosolic proteins.ome of which attach to the flavocytochrome. P47phox.67phox and p40phox arespecialised components of phagocytic cells.ll of which contain SH3domains .y means of which they attach to proline-rich regions of otherproteins. Upon activation.47phox and p67phox are phosphorylated and.ith p40phox.ranslocate to the region of the plasma membrane formingthe phagocytic they associates with hydrophilic regionsof the flavocytochrome .
  IPR000108:Neutrophil cytosol factor 2
The Rho family GTPases and CDC42 regulate a diverse array of cellularprocesses. Like all members of the Ras superfamily.he Rho proteins cycle between active GTP-bound and inactive GDP-bound conformational states.Activation of Rho proteins through release of bound GDP and subsequentbinding of GTP.s catalyzed by guanine nucleotide exchange factors (GEFs) inthe Dbl family. The proteins encoded by members of the Dbl family share acommon domain.resented in this entry.f about 200 residues (designated the Dbl homology or DH domain)that has been shown to encode a GEF activity specific for a number of Rhofamily members. In addition.ll family members possess a second.hareddomain designated the pleckstrin homology (PH) domain (). Trioand its homolog UNC-73 are unique within the Dbl family insomuch as theyencode two distinct DH/PH domain modules. The PH domain is invariably locatedimmediately C-terminal to the DH domain and this invariant topography suggestsa functional interdependence between these two structural modules. Biochemicaldata have established the role of the conserved DH domain in Rho GTPaseinteraction and activation.nd the role of the tandem PH domain inintracellular targeting and/or regulation of DH domain function. The DH domainof Dbl has been shown to mediate oligomerization that is mostly homophilic innature. In addition to the tandem DH/PH domains Dbl family GEFs containdiverse structural motifs like serine/threonine kinase.BD.DZ.GS.Q.EM.dc25RasGEF.H.H2.H3.F.pectrin or Ig.The DH domain is composed of three structurally conserved regions separated bymore variable regions. It does not share significant sequence homology withother subtypes of small G-protein GEF motifs such as the Cdc25 domain and theSec7 domain.hich specifically interact with Ras and ARFfamily small GTPases.espectively.or with other Rho protein interactivemotifs.ndicating that the Dbl family proteins are evolutionarily unique. TheDH domain is composed of 11 alpha helices that are folded into a flattened.longated alpha-helix bundle in which two of the three conserved regions.onserved region 1 (CR1) and conserved region 3 (CR3).re exposed near thecenter of one surface. CR1 and CR3.ogether with a part of alpha-6 and theDH/PH junction site.onstitute the Rho GTPase interacting pocket.
SH3 (src Homology-3) domains are small protein modules containing approximately 50 amino acid residues . They are found in a great variety of intracellular or membrane-associated proteins for example.n a variety of proteins with enzymatic activity.n adaptor proteins that lack catalytic sequences and in cytoskeletal proteins.uch as fodrin and yeast actin binding protein ABP-1. The SH3 domain has a characteristic fold which consists of five or six beta-strands arranged as two tightly packed anti-parallel beta sheets. The linker regions may contain short helices . The surface of the SH2-domain bears a flat.ydrophobic ligand-binding pocket which consists of three shallow grooves defined by conservative aromatic residues in which the ligand adopts an extended left-handed helical arrangement. The ligand binds with low affinity but this may be enhanced by multiple interactions.The region bound by the SH3 domain is in all cases proline-rich and contains PXXP as a core-conserved binding motif. The function of the SH3 domain is not well understood but they may mediate many diverse processes such as increasing local concentration of proteins.ltering their subcellular location and mediating the assembly of large multiprotein complexes .
  IPR001452:Src homology-3
Pleckstrin homology (PH) domains are small modular domains that occur once.r occasionally several times.n a large variety of signalling they serve as simple targeting domains that recognize only phosphoinositide headgroups . PH domains can target their host protein to the plasma and internal membranes through its association with phosphoinositides. PH domains have a partly opened beta-barrel topology that is capped by an alpha helix. Proteins containing PH domains include pleckstrin (N-terminal).hospholipase C and Rac-alpha kinase.The structure of PH domains is similar to the phosphotyrosine-binding domain (PTB) found in IRS-1 (insulin receptor substrate 1).hc adaptor and Numb; to the Ran-binding domain.ound in Nup nuclear pore complex and Ranbp1; to the Enabled/VASP homology domain 1 (EVH1 domain).ound in Enabled.ASP (vasodilator-stimulated phosphoprotein).omer and WASP actin regulatory protein; to the third domain of FERM.ound in moesin.adixin.zrin.erlin and talin; and to the PH-like domain of neurobeachin.
  IPR011993:Pleckstrin homology-type
Spectrin is an elongated protein that belongs to a family of related molecules (including dystrophin and alpha-actinin) that contain tandemly repeated segments and form resilient cellular meshworks by cross-linking actin filaments . The protein is an alpha-beta heterodimer in which the alpha and beta monomers associate in an anti-parallel fashion . Assembly involves initial contact of complementary nucleation sites on each subunit.ia four tandem repeat regions . Following nucleation.he remainder of the subunits associate rapidly along their full lengths to form a dimer by super-coiling around each other.orming a rope-like.lexible rod . Assembly terminates if either polypeptide is interrupted by protease cleavage. Heterozygotic mutations involving either nucleation site are predicted to affect allele incorporation into the mature membrane skeleton . The structure of a repeat unit of alpha-spectrin has been determined to 1.8A resolution by means of X-ray crystallography . This was shown to comprise an anti-parallel three-helix bundle separated by two loops.hich folds into a left-handed coiled coil . At the interface between tandem repeats.ydrophobic interactions may constrain intersegment flexibility. The interaction between alpha- and beta-subunits is mediated by the association of two helices at the C-terminus of the beta-chain and a single helix from the N-terminus of the alpha-chain. Mutations that affect these critical helix side-chain interactions disrupt spectrin associations that sustain the integrity of erythrocyte membranes giving rise to haemolytic anaemias . These haemolytic syndromes include hereditary elliptocytosis.ts aggravated form hereditary pyropoikilocytosis and hereditary spherocytosis .
  IPR013315:Spectrin alpha chain
SequencesProtein: ITSN1_HUMAN (1721 aa)
mRNA: NM_003024
Local Annotation
Synapse Ontology
introduce the substructure of the synapse and the location where the molecule can be seen. It will contain all the constructive special organelle and molecule we known.
sdb:0001 Structure/Biochemistry of synapse  (Evidence:keywords)
A clathrin coat found on a synaptic vesicle.
sdb:0076 clathrin coat of synaptic vesicle  (Evidence:keywords)
Various stages of the synaptic vesicle cycle, including attachment, prefusion, triggering, recycling and reloading of the vesicles with transmitter.
sdb:0098 synaptic vesicle cycling  (Evidence:keywords)
priming for exocytosis prepares the calcium-dependent release and may involve partial fusion process. The vesicles are primed and become responsive to calcium.
sdb:0120 priming  (Evidence:keywords)
attachment of the vesicle filled with transmitters involves a specific interaction between the vesicle membrane and the presynaptic active zone.
sdb:0148 docking  (Evidence:keywords)
endocytosis may be initiated or blocked by all kinds of signal.
sdb:0257 regulation of endocytosis  (Evidence:keywords)
all the components of the clathrin coat, major ones are clathrin and clathrin adaptors.
sdb:0261 clathrin coat component  (Evidence:keywords)
sdb:0329 actin in synaptic vesicle cycling  (Evidence:keywords)
KO assignmentNot mapped to KEGG
Loci Structure (Details)Loci index, Chromosomal location, Length, Possible relational loci clusterExon1: 79 residues, 33936653-33936889Exon2: 22 residues, 34012971-34013031Exon3: 33 residues, 34015352-34015445Exon4: 23 residues, 34016762-34016826Exon5: 55 residues, 34029218-34029379Exon6: 62 residues, 34044317-34044497Exon7: 34 residues, 34045984-34046081Exon8: 35 residues, 34049471-34049572Exon9: 23 residues, 34056096-34056160Exon10: 48 residues, 34060048-34060186Exon11: 40 residues, 34061886-34062002Exon12: 89 residues, 34066234-34066497Exon13: 52 residues, 34068902-34069052Exon14: 49 residues, 34069141-34069282Exon15: 31 residues, 34075634-34075722Exon16: 48 residues, 34076167-34076307Exon17: 44 residues, 34088514-34088642Exon18: 78 residues, 34091552-34091782Exon19: 42 residues, 34093981-34094103Exon20: 7 residues, 34096603-34096618Exon21: 84 residues, 34105148-34105396Exon22: 55 residues, 34108086-34108246Exon23: 70 residues, 34112440-34112646Exon24: 29 residues, 34113414-34113497Exon25: 57 residues, 34117660-34117827Exon26: 17 residues, 34120991-34121037Exon27: 42 residues, 34123797-34123919Exon28: 41 residues, 34128480-34128598Exon29: 66 residues, 34130614-34130806Exon30: 42 residues, 34150909-34151031Exon31: 37 residues, 34152859-34152966Exon32: 63 residues, 34159324-34159508Exon33: 35 residues, 34161406-34161505Exon34: 58 residues, 34169527-34169695Exon35: 73 residues, 34176416-34176629Exon36: 42 residues, 34177723-34177845Exon37: 29 residues, 34179214-34179297Exon38: 30 residues, 34179612-34179696Exon39: 60 residues, 34180460-34180634Exon40: 386 residues, 34182325-34183479Exon41: 2 residues, -Jump to ITSN1_HUMAN  
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Loci Cluster (Details)Loci: 4549 34197627-34210028 ~-12K 23791(ATP5O)(-)Loci: 3287 34367692-34437198 ~-70K 23793(MRPS6)(+)Loci: 3286 33936653-34183479 ~-247K 23790(ITSN1)(+)Link out to UCSC