PROSITE documentation PDOC00351

Disintegrin domain signature and profile

Disintegrins [1,2] are snake venom proteins which inhibit fibrinogen interaction with platelet receptors expressed on the glycoprotein IIb-IIIa complex. They act by binding to the integrin glycoprotein IIb-IIIa receptor on the platelet surface and inhibit aggregation induced by ADP, thrombin, platelet-activating factor and collagen.

Disintegrins are peptides of about 70 amino acid residues that contain many cysteines all involved in disulfide bonds [3]. Disintegrins contain an Arg-Gly-Asp (RGD) sequence, a recognition site of many adhesion proteins. The RGD sequence of disintegrins is postulated to interact with the glycoprotein IIb-IIIa complex.

The sequences of disintegrins from different snake species are known. These proteins are known as: albolabrin, applagin, barbourin, batroxostatin, bitistatin, echistatin, elegantin, eristicophin, flavoridin, halysin, kistrin, tergeminin and triflavin.

Some other proteins are known to contain a disintegrin domain:

• Some snake venom zinc metalloproteinases [4] 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.
• ADAM type metalloproteases (see <PDOC50215>).
• Mammalian epididymial protein 1 (EAP I) [6]. 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.

The schematic representation of the structure of a typical disintegrin domain is shown below:

                              +-----+
                +-------------|-----|--+        +------------------+
                |             |     |  |        |                  |
  xxxxxCxCxxxxxxCCxxxxCxxxxxxxCxxxxCCxxCxxxxxxxxCxxxRGDxxxxxCxxxxxxCxxxxxxx
       | |       |    |       *****|**************          |
       +-|-------|----+            +------------------------+
         +-------+

'C': conserved cysteine involved in a disulfide bond.
'*': position of the pattern.

Short disintegrins lack the N-terminal of the domain.

As a signature pattern for the disintegrin domain, we selected a conserved central region that contains five of the cysteines involved in disulfide bonds. A profile was also developed that spans the whole domain.