Taxonomic distribution of proteins containing DISIN domains

The tree below includes only several representative species and genera. The complete taxonomic breakdown of all proteins containing DISIN domains can be accessed here. Click the counts or percentage values to display the corresponding proteins.

A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells.

Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP
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.

Rotavirus contains integrin ligand sequences and a disintegrin-like domain that are implicated in virus entry into cells.

Coulson BS, Londrigan SL, Lee DJ
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.

Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha.

Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Becherer JD, etal.
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.

Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis.

Pan D, Rubin GM
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.

ADAMs and cell fusion.

Huovila AP, Almeida EA, White JM
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.

KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis.

Rooke J, Pan D, Xu T, Rubin GM
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.

Structure, function and evolutionary relationship of proteins containing a disintegrin domain.

Blobel CP, White JM
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.