Crystal structure of the membrane-proximal ectodomain of the phogrin receptor.

MARTIN E. NOGUERA; MARIA E. PRIMO; EDGARDO POSKUS ; MARIO R. ERMACORA

Tafi del Valle

Congreso; XLI Reunión Anual de la Sociedad Argentina de Biofísica; 2012

Sociedad Argentina de Biofísica

The receptor-type protein-tyrosine phosphatase (RPTP) phogrin is localized in the secretory granules of pancreatic beta-cells, and plays a role in the regulation of insulin secretion and beta-cell growth. The mature receptor comprises an ectodomain, a transmembrane domain, and the cytoplasmic tail including the inactive phosphatase domain. Phogrin shares these features with ICA512, another member of the RPTP family. Nevertheless, their expression profile is dissimilar: ICA512 expression increases during development and is influenced by glucose and other agents, whereas phogrin expression is constant and not significantly affected by glucose levels1. With the ultimate goal of to understand the biological function of these proteins at the molecular level, we perform biophysical and structural studies of its membrane-proximal ectodomain (MPE). In the present work, the crystal structure of the recombinant MPE phogrin was determined by molecular replacement using the coordinates of MPE ICA512, and refined to 1.95 Å. Both proteins exhibit a typical ferredoxin-like (βαββαβ) fold, however, while recombinant MPE ICA512 is dimeric in solution and its x-ray structure revealed several association modes, MPE phogrin is monomeric in solution and the crystal contained only one protein molecule in the asymmetric unit. Homo- and hetero-dimerization are considered important for the RPTP family of proteins. This study establishes several common features and differences between MPE phogrin and MPE ICA512, what should to shed some light on the molecular details of its biological function.