Disintegrin family

General Disintegrins are a family of low molecular weight, non-enzymatic, cysteine rich proteins that bind to integrins and are present in venom of Viperidae and Crotalidae.

Disintegrin-like proteins are also found in various species ranging from slime mold to humans. They are evolutionary close to the ADAM family, an ancestral protein family that contains at least the two domains disintegrin and metalloproteinase (ADAM means "A Disintegrin And Metalloproteinase") (Juarez et al., 2008).

Disintegrins have the ability to bind integrins which are heterodimeric receptors present on the cell surface. Integrins interact with components of the basement membrane such as collagen IV and laminin, with adhesive proteins present in the extracellular matrix (vitronectin, fibronectin, collagen I and III), or in the blood (fibrinogen, von Willebrand factor), or with membrane-bound counter-receptors on other cells. Integrins are involved in many physiological and pathological processes including platelet aggregation, cell migration, immune response, wound healing, tumor invasion, angiogenesis, inflammation and bone remodeling (McLane et al., 2008).

Disintegrins possess an integrin-binding motif (most often RGD) that is located near the C-terminus at the tip of a flexible hairpin loop. The binding-motif aspartate residue might be responsible for binding to integrin, whereas the other two residues (RG, MG, WG, ML, VG) may dictate the integrin specificity (Xiong et al., 2002, Calvete et al., 2003).

Most of disintegrins inhibit platelet aggregation. They act by binding to αIIbβ3 integrin on activated platelets, thus preventing its interaction with fibrinogen (Sajevic et al., 2011).

The table 1 below shows the motifs of the disintegrins and their integrin targets.

Motif	Target integrin	Reference
RGD	αIIb/β3, α8/β1, α5/β1, αV/β1, αV/β3
KGD	αIIb/β3	Scarborough et al., 1991
MGD	α5/β1	Marcinkiewicz et al., 1999
VGD	α5/β1	Calvete et al., 2003, Marcinkiewicz et al., 1999
WGD	α5/β1, αV/β3, αIIb/β3	Calvete et al., 2002
MLD	α3/β1, α4/β1, α4/β7, α6/β1, α7/β1, α9/β1, αV/β6	Eble et al., 2003, Calvete et al., 2007, Calvete et al., 2003, Marcinkiewicz et al., 2000, Marcinkiewicz et al., 1999
MVD	probably αIIb/β3	Shimokawa et al., 1998
KTS	α1/β1	Dariusz et al., 2004, Calvete et al., 2007
RTS	α1/β1	Sanz et al., 2005
TDN	?	Camacho et al., 2014

Structure
Depending on the length of polypeptide chain and the number of disulfide bonds, they are divided into five different groups including short-, medium-, long-chain disintegrins, dimeric disintegrins, and disintegrin-like domains of the P-III subfamily (which have D/ECD motifs) of snake venom metalloproteases (SVMPs). These different classes are represented in the table 2 below.

Class	Amino acids length	Number of cysteines
Short disintegrin	41-51	8
Medium disintegrin	about 70	12
Long disintegrin	about 84	14
Dimeric disintegrin	about 67	10
P-III disintegrin-like	~100 in the dis-like domain (D) 110-120 in the Cys-rich domain ( C)	16 in the dis-like domain 12 in the Cys-rich domain