Crystal structure of a phospholipase A(2) from Bothrops asper venom: Insights into a new putative "myotoxic cluster"

Author(s)

Salvador, Guilherme H. M. ; dos Santos, Juliana I. ; Lomonte, Bruno ; Fontes, Marcos R. M.

• Document type: Journal article
• Source: Biochimie; v. 133, p. 8-pg., 2017-02-01.

Abstract

Snake venoms from the Viperidae and Elapidae families often have several phospholipases A(2) (PLA(2)s), which may display different functions despite having a similar structural scaffold. These proteins are considered an important target for the development of drugs against local myotoxic damage because they are not efficiently neutralized by conventional serum therapy. PLA(2)s from these venoms are generally divided into two classes: (i) catalytic PLA(2)s (or Asp49-PLA(2)s) and (ii) non-catalytic PLA(2)-like toxins (or Lys49-PLA(2)s). In many Viperidae venoms, a subset of the basic Asp49-PLA2s displays some functional and structural characteristics of PLA(2)-like proteins and group within the same phylogenetic Glade, but their myotoxic mechanism is still largely unknown. In the present study, we have crystallized and solved the structure of myotoxin I (MT-I), a basic myotoxic Asp49-PLA(2) isolated from Bothrops asper venom. The structure presents a dimeric conformation that is compatible with that of previous dimers found for basic myotoxic Asp49-PLA(2)s and Lys49-PLA(2)s and has been confirmed by other biophysical and bioinformatics techniques. This arrangement suggests a possible cooperative action between both monomers to exert myotoxicity via two different sites forming a putative membrane-docking site (MDoS) and a putative membrane disruption site (MDiS). This mechanism would resemble that proposed for Lys49-PLA(2)s, but the sites involved appear to be situated in a different region. Thus, as both sites are close to one another, they form a "myotoxic cluster", which is also found in two other basic myotoxic Asp49-PLA(2)s from Viperidae venoms. Such arrangement may represent a novel structural strategy for the mechanism of muscle damage exerted by the group of basic, Asp49-PLA(2)s found in viperid snake venoms. (C) 2016 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. (AU)

• FAPESP's process: 15/17286-0 - Structural and functional studies aiming to understand the role of snake venoms toxins and how to inhibit their biological activity
• Grantee: Marcos Roberto de Mattos Fontes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/24167-7 - STRUCTURAL STUDIES OF PROTEINS INVOLVED TO LOCAL MUSCULAR NECROSIS IN BOTHROPIC ACCIDENTS
• Grantee: Guilherme Henrique Marchi Salvador
• Support Opportunities: Scholarships in Brazil - Post-Doctoral