The domain within your query sequence starts at position 426 and ends at position 501; the E-value for the DISIN domain shown below is 9.7e-41.

EDGEECDCGEEEECKNPCCNASNCTLKEGAECAHGSCCHQCKLVAPGTQCREQVRQCDLP
EFCTGKSPHCPTNYYQ

DISIN

Homologues of snake disintegrins

• SMART accession number: SM00050
• Description: Snake disintegrins inhibit the binding of ligands to integrin receptors. They contain a 'RGD' sequence, identical to the recognition site of many adhesion proteins. Molecules containing both disintegrin and metalloprotease domains are known as ADAMs.
• Interpro abstract (IPR001762):

  Disintegrins are a family of small proteins from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion [ (PUBMED:15578957) (PUBMED:15974889) ]. Integrin receptors are involved in cell-cell and cell-extracellular matrix interactions, serving as the final common pathway leading to aggregation via formation of platelet-platelet bridges, which are essential in thrombosis and haemostasis. Disintegrins contain an RGD (Arg-Gly-Asp) or KGD (Lys-Gly-Asp) sequence motif that binds specifically to integrin IIb-IIIa receptors on the platelet surface, thereby blocking the binding of fibrinogen to the receptor-glycoprotein complex of activated platelets. Disintegrins act as receptor antagonists, inhibiting aggregation induced by ADP, thrombin, platelet-activating factor and collagen [ (PUBMED:12050803) ]. The role of disintegrin in preventing blood coagulation renders it of medical interest, particularly with regard to its use as an anti-coagulant [ (PUBMED:16918409) ].

  Disintegrins from different snake species have been characterised: albolabrin, applagin, barbourin, batroxostatin, bitistatin, obtustatin [ (PUBMED:12742023) ], schistatin [ (PUBMED:16101289) ], echistatin [ (PUBMED:15535803) ], elegantin, eristicophin, flavoridin [ (PUBMED:14499613) ], halysin, kistrin, tergeminin, salmosin [ (PUBMED:14661951) ] and triflavin.

  Disintegrin-like proteins are found in various species ranging from slime mold to humans. Some other proteins known to contain a disintegrin domain are:

  • Some snake venom zinc metalloproteinases [ (PUBMED:15962120) ] consist of an N-terminal catalytic domain fused to a disintegrin domain. Such is the case for trimerelysin I (HR1B), atrolysin-e (Ht-e) and trigramin. It has been suggested that these proteinases are able to cleave themselves from the disintegrin domains and that the latter may arise from such a post-translational processing.
  • The beta-subunit of guinea pig sperm surface protein PH30 [ (PUBMED:1552944) ]. PH30 is a protein involved in sperm-egg fusion. The beta subunit contains a disintegrin at the N-terminal extremity.
  • Mammalian epididymial apical protein 1 (EAP I) [ (PUBMED:1417724) ]. EAP I is associated with the sperm membrane and may play a role in sperm maturation. Structurally, EAP I consists of an N-terminal domain, followed by a zinc metalloproteinase domain, a disintegrin domain, and a large C-terminal domain that contains a transmembrane region.

There are 12250 DISIN domains in 12145 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Black RA et al.
• A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells.
• Nature. 1997; 385: 729-33

Mammalian cells proteolytically release (shed) the extracellular domains of many cell-surface proteins. Modification of the cell surface in this way can alter the cell's responsiveness to its environment and release potent soluble regulatory factors. The release of soluble tumour-necrosis factor-alpha (TNF-alpha) from its membrane-bound precursor is one of the most intensively studied shedding events because this inflammatory cytokine is so physiologically important. The inhibition of TNF-alpha release (and many other shedding phenomena) by hydroxamic acid-based inhibitors indicates that one or more metalloproteinases is involved. We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. Inactivation of the gene in mouse cells caused a marked decrease in soluble TNF-alpha production. This enzyme (called the TNF-alpha-converting enzyme, or TACE) is a new member of the family of mammalian adamalysins (or ADAMs), for which no physiological catalytic function has previously been identified. Our results should facilitate the development of therapeutically useful inhibitors of TNF-alpha release, and they indicate that an important function of adamalysins may be to shed cell-surface proteins.

• Coulson BS, Londrigan SL, Lee DJ
• Rotavirus contains integrin ligand sequences and a disintegrin-like domain that are implicated in virus entry into cells.
• Proc Natl Acad Sci U S A. 1997; 94: 5389-94

Rotavirus contains two outer capsid viral proteins, the spike protein VP4 and major capsid component VP7, both of which are implicated in cell entry. We show that VP4 and VP7 contain tripeptide sequences previously shown to act as recognition sites for integrins in extracellular matrix proteins. VP4 contains the alpha2beta1 integrin ligand site DGE. In VP7, the alphaxbeta2 integrin ligand site GPR and the alpha4beta1 integrin ligand site LDV are embedded in a novel disintegrin-like domain that also shows sequence similarity to fibronectin and the tie receptor tyrosine kinase. Microorganism sequence homology to these ligand motifs and to disintegrins has not been reported previously. In our experiments, peptides including these rotaviral tripeptides and mAbs directed to these integrins specifically blocked rotavirus infection of cells shown to express alpha2beta1 and beta2 integrins. Rotavirus VP4-mediated cell entry may involve the alpha2beta1 integrin, whereas VP7 appears to interact with alphaxbeta2 and alpha4beta1 integrins.

• Moss ML et al.
• Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha.
• Nature. 1997; 385: 733-6

Tumour-necrosis factor-alpha (TNF-alpha) is a cytokine that contributes to a variety of inflammatory disease states. The protein exists as a membrane-bound precursor of relative molecular mass 26K which can be processed by a TNF-alpha-converting enzyme (TACE), to generate secreted 17K mature TNF-alpha. We have purified TACE and cloned its complementary DNA. TACE is a membrane-bound disintegrin metalloproteinase. Structural comparisons with other disintegrin-containing enzymes indicate that TACE is unique, with noteable sequence identity to MADM, an enzyme implicated in myelin degradation, and to KUZ, a Drosophila homologue of MADM important for neuronal development. The expression of recombinant TACE (rTACE) results in the production of functional enzyme that correctly processes precursor TNF-alpha to the mature form. The rTACE provides a readily available source of enzyme to help in the search for new anti-inflammatory agents that target the final processing stage of TNF-alpha production.

• Pan D, Rubin GM
• Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis.
• Cell. 1997; 90: 271-80

Notch and the disintegrin metalloprotease encoded by the kuzbanian (kuz) gene are both required for a lateral inhibition process during Drosophila neurogenesis. We show that a mutant KUZ protein lacking protease activity acts as a dominant-negative form in Drosophila. Expression of such a dominant-negative KUZ protein can perturb lateral inhibition in Xenopus, leading to the overproduction of primary neurons. This suggests an evolutionarily conserved role for KUZ. The Notch family of receptors are known to be processed into smaller forms under normal physiological conditions. We provide genetic and biochemical evidence that Notch is an in vivo substrate for the KUZ protease, and that this cleavage may be part of the normal biosynthesis of functional Notch proteins.

• Huovila AP, Almeida EA, White JM
• ADAMs and cell fusion.
• Curr Opin Cell Biol. 1996; 8: 692-9

Members of the ADAM family (membrane proteins with a disintegrin and metalloprotease domain) have been implicated in several cell-interactive events, including cell-cell fusion. Recent evidence implicates three ADAMs, fertilin-alpha, fertilin-beta, and meltrin-alpha, in sperm-egg fusion and myoblast fusion. In light of the large number and wide tissue distribution of the ADAMs, they may also participate in other cell-cell fusion events. As ADAMs are also found in both vertebrates and invertebrates, some features of cell-cell fusion reactions may be conserved throughout the animal kingdom.

• Rooke J, Pan D, Xu T, Rubin GM
• KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis.
• Science. 1996; 273: 1227-31

During neurogenesis in Drosophila both neurons and nonneuronal cells are produced from a population of initially equivalent cells. The kuzbanian (kuz) gene described here is essential for the partitioning of neural and nonneuronal cells during development of both the central and peripheral nervous systems in Drosophila. Mosaic analyses indicated that kuz is required for cells to receive signals inhibiting the neural fate. These analyses further revealed that the development of a neuron requires a kuz-mediated positive signal from neighboring cells. The kuz gene encodes a metalloprotease-disintegrin protein with a highly conserved bovine homolog, raising the possibility that kuz homologs may act in similar processes during mammalian neurogenesis.

• Blobel CP, White JM
• Structure, function and evolutionary relationship of proteins containing a disintegrin domain.
• Curr Opin Cell Biol. 1992; 4: 760-5

Disintegrins are soluble integrin ligands from snake venoms that disrupt cell-matrix interactions. Recently, the nuclear magnetic resonance structures of two disintegrins were determined, providing provocative molecular insight into how a disintegrin may engage an integrin. In addition, it has recently been realized that disintegrins are derived from larger multifunctional proteins, and that there is a family of membrane-anchored, disintegrin domain-containing proteins that may promote important cell-cell interactions.

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
69.70	map05120	Epithelial cell signaling in Helicobacter pylori infection
30.30	map04330	Notch signaling pathway

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with DISIN domain which could be assigned to a KEGG orthologous group, and not all proteins containing DISIN domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of DISIN domains in PDB

PDB code	Title
1fvl	THE NUCLEAR MAGNETIC RESONANCE SOLUTION STRUCTURE OF FLAVORIDIN, AN ANTAGONIST OF THE PLATELET GP IIB-IIIA RECEPTOR
1j2l	Crystal structure of the disintegrin, trimestatin
1l3x	Solution Structure of Novel Disintegrin Salmosin
1mpz	NMR solution structure of native Viperidae lebetina obtusa protein
1n4y	REFINED STRUCTURE OF KISTRIN
1q7i	Structural Analysis of Integrin alpha IIb beta 3- Disintegrin with the AKGDWN Motif
1q7j	Structural Analysis of Integrin alpha IIb beta 3- Disintegrin with the AKGDWN Motif
1rmr	Crystal Structure of Schistatin, a Disintegrin Homodimer from saw-scaled Viper (Echis carinatus) at 2.5 A resolution
1ro3	New structural insights on short disintegrin echistatin by NMR
1tej	Crystal structure of a disintegrin heterodimer at 1.9 A resolution.
1z1x	Crystal Structure of a novel disintegrin from Saw-scaled viper at 3.2 A resolution
2ao7	Adam10 Disintegrin and cysteine- rich domain
2dw0	Crystal structure of VAP2 from Crotalus atrox venom (Form 2-1 crystal)
2dw1	Crystal structure of VAP2 from Crotalus atrox venom (Form 2-2 crystal)
2dw2	Crystal structure of VAP2 from Crotalus atrox venom (Form 2-5 crystal)
2e3x	Crystal structure of Russell's viper venom metalloproteinase
2ech	ECHISTATIN-THE REFINED STRUCTURE OF A DISINTEGRIN IN SOLUTION BY 1H NMR
2ero	Crystal structure of vascular apoptosis-inducing protein-1(orthorhombic crystal form)
2erp	Crystal structure of vascular apoptosis-inducing protein-1(inhibitor-bound form)
2erq	Crystal structure of vascular apoptosis-inducing protein-1(tetragonal crystal form)
2ljv	Solution structure of Rhodostomin G50L mutant
2m75	The C-terminal Region of Disintegrin Modulate its 3D Conformation and Cooperate with RGD Loop in Regulating Recognitions of Integrins
2m7f	The C-terminal Region of Disintegrin Modulate its 3D Conformation and Cooperate with RGD Loop in Regulating Integrins Recognitions
2m7h	The C-terminal Region of Disintegrin Modulate its 3D Conformation and Cooperate with RGD Loop in Regulating Integrin alpha-IIb beta-3 Recognition
2mop	2MOP
2mp5	2MP5
2pjf	Solution structure of rhodostomin
2pjg	Solution structure of rhodostomin D51E mutant
2pji	Solution structure of rhodostomin P48A mutant
2w9o	Solution structure of jerdostatin from Trimeresurus jerdonii
2w9u	Solution structure of jerdostatin mutant R24K from Trimeresurus jerdonii
2w9v	Solution structure of jerdostatin from Trimeresurus jerdonii with end C-terminal residues N45G46 deleted
2w9w	Solution structure of jerdostatin mutant R24K from Trimeresurus jerdonii with end C-terminal residues N45G46 deleted
3c05	Crystal structure of Acostatin from Agkistrodon Contortrix Contortrix
3dsl	The Three-dimensional Structure of Bothropasin, the Main Hemorrhagic Factor from Bothrops jararaca venom.
3g5c	Structural and biochemical studies on the ectodomain of human ADAM22
3hdb	Crystal structure of AaHIV, A metalloproteinase from venom of Agkistrodon Acutus
3k7l	Structures of two elapid snake venom metalloproteases with distinct activities highlight the disulfide patterns in the D domain of ADAMalysin family proteins
3k7n	Structures of two elapid snake venom metalloproteases with distinct activities highlight the disulfide patterns in the D domain of ADAMalysin family proteins
3uci	Crystal structure of Rhodostomin ARLDDL mutant
4m4c	4M4C
4r5r	4R5R
4r5u	4R5U
4rqg	4RQG
5l0q	5L0Q

Links (links to other resources describing this domain)

• INTERPRO: IPR001762
• PFAM: disintegrin
• PROSITE: DISIN_DOMAIN