Poster #RP216
Structural model of ADAMs disintegrin-like domain and dynamics of interaction with Alpha6Beta1.
Monika Aparecida Coronado*, Aline Rossi Silveira*, Wilson Savino**, Ana Tereza Ribeiro Vasconcelos*, Jorge Hernandez Fernandez*
*LNCC - Laboratório Nacional de Computação Científica, Petrópolis, Brazil; **Fiocruz - Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
ADAM proteins are family of transmembrane glycoproteins from zinc protease superfamily. They have a modular design, characterized by the presence of metalloprotease, integrin receptor-binding activities, and a cytoplasmic domain that specifies binding sites for signal transducing proteins. These proteins have been implicated in cytokine and growth factor shedding, cell migration, processes of fertilization, inflammation, cancer and cell fate determination. The ADAM disintegrin domain is homologous to snake venom disintegrins and potential integrin ligand. Based on sequence similarity, disulfide bond pattern and evolutionary relationship, the structure of salmosin and flavoridin snake venom disintegrins were used to model the disintegrin domain of fertilin beta (ADAM2) and meltrin gama (ADAM9). Molecular modeling and dynamics were used to obtain a detailed interaction model of ADAM-alpha6beta1 integrin complex. Since the XECD integrin binding motif in ADAM was placed in a loop structure protruding from the core as snake venom disintegrin RGD motif, additional C-terminal disulfide bond in ADAM implicate in an increase of conformational constrains for the binding loops. The dynamics of integrin binding in ADAM was initially drived by electrostatic interactions, but conformation of binding loop was different in final integrin recognition for RGD snake venom disintegrin and ADAM domains.
Funded by CNPq/Capes/MCT