Structure-Function Relationship of the Disintegrin Family: Sequence Signature and Integrin Interaction.

Ariana A Vasconcelos,Jorge C Estrada,Russolina B Zingali,Victor David,Luciana S Wermelinger,Fabio C L Almeida

doi:10.3389/fmolb.2021.783301

Abstract

Disintegrins are small cysteine-rich proteins found in a variety of snake venom. These proteins selectively modulate integrin function, heterodimeric receptors involved in cell-cell and cell-matrix interaction that are widely studied as therapeutic targets. Snake venom disintegrins emerged from the snake venom metalloproteinase and are classified according to the sequence size and number of disulfide bonds. Evolutive structure and function diversification of disintegrin family involves a stepwise decrease in the polypeptide chain, loss of cysteine residues, and selectivity. Since the structure elucidation of echistatin, the description of the structural properties of disintegrins has allowed the investigation of the mechanisms involved in integrin-cell-extracellular matrix interaction. This review provides an analysis of the structures of all family groups enabling the description of an expanded classification of the disintegrin family in seven groups. Each group presents a particular disulfide pattern and sequence signatures, facilitating the identification of new disintegrins. The classification was based on the disintegrin-like domain of the human metalloproteinase (ADAM-10). We also present the sequence and structural signatures important for disintegrin-integrin interaction, unveiling the relationship between the structure and function of these proteins.

Highlights

Integrin antagonists comprise molecules that can bind and interfere with the activity of the cellular receptors integrins
Disintegrins are divided into five different groups according to their polypeptide length and the number of disulfide bonds
Through comparing amino acid sequences by multiple-sequence alignment, a brief phylogenetic analysis, and extensive literature review, we support the view that the different disintegrin subfamilies evolved from a common A Disintegrin And Metalloproteinase (ADAM) and that structural diversification occurred through disulfide bond engineering

Summary

INTRODUCTION

Integrin antagonists comprise molecules that can bind and interfere with the activity of the cellular receptors integrins. We propose an expanded classification based on the structural features of disintegrins and use the disintegrin-like domain of a PIII ADAM as a reference for folding and disulfide pattern. Jarastatin and triflavin disintegrins contain six disulfide bonds with the same cysteine pattern while the disintegrin domain of ADAM metalloproteinases present the same size, structural homology, and different disulfide pattern (Huang T.-F. et al, 1991; Coelho et al, 1999; Cidade et al, 2006). The letter-based pattern is defined as AE BC DJ F GI HM L kN, where F and L, which appear here unmatched, are cysteines involved in connections with the other domains This group is formed by mammalian (ADAM) and snake venom metalloproteinases (SVMP), both containing the disintegrin domain with the same fold.

G2 G3 G4 G5 G6 G7A G7B

Findings

CONCLUSION AND FUTURE DIRECTIONS