Authors: Jonathan P Schlebach Charles R Sanders
Publish Date: 2014/09/06
Volume: 248, Issue: 3, Pages: 371-381
Abstract
Aberrant protein folding and assembly contribute to a number of diseases and efforts to rationalize how pathogenic mutations cause this phenomenon represent an important imperative in biochemical research However for αhelical membrane proteins this task is complicated by the fact that membrane proteins require intricate machinery to achieve structural and functional maturity under cellular conditions In this work we utilized the ΔG predictor algorithm wwwdgpredcbrsuse to survey 470 known pathogenic mutations occurring in five misfoldingprone αhelical membrane proteins for their predicted effects on the transloconmediated membrane integration of transmembrane helices a critical step in biosynthesis and folding of nascent membrane proteins The results suggest that about 10 of these mutations are likely to have adverse effects on the topogenesis of nascent membrane proteins These results suggest that the misfolding of a modest but nonetheless significant subset of pathogenic variants may begin at the translocon Potential implications for therapeutic design and personalized medicine are discussed
Keywords: