A computational approach to the investigation of aggregation prone regions in serine protease inhibitors

Friday, November 08, 2013 — Poster Session IV
2:00 p.m. – 4:00 p.m.	FAES Academic Center (Upper-Level Terrace)	FDA/CBER	COMPBIO-20

Authors

C Stuart
W Gwizdala
J Niewczas
W Jong
D Scott
E Marszal

Abstract

Protein aggregation underlies many human diseases and can hinder the manufacture of safe and effective biotherapeutics. Members of the serpin superfamily of proteins are particularly prone to aggregation, owing to their metastable native structure, and the formation and structure of serpin polymers is highly debatable despite over 20 years of research. We used a computational method, Tango, to predict aggregation prone regions in a diverse set of serpins, and to compare the regions identified to those implicated in previously proposed models of serpin polymerization. We found several aggregation prone regions to be conserved throughout the serpins, and explored potential roles of aggregation propensity in serpin folding de novo, function, and subcellular localization. Our results contribute to the understanding of the competition between the mechanisms of folding and aggregation, as well as support additional roles of aggregation prone regions, all of which have implications in the development of safe and effective protein products.