MCSM-membrane: predicting the effects of mutations on transmembrane proteins.

Carlos H M Rodrigues,David B Ascher,Douglas E V Pires

doi:10.1093/nar/gkaa416

Abstract

Significant efforts have been invested into understanding and predicting the molecular consequences of mutations in protein coding regions, however nearly all approaches have been developed using globular, soluble proteins. These methods have been shown to poorly translate to studying the effects of mutations in membrane proteins. To fill this gap, here we report, mCSM-membrane, a user-friendly web server that can be used to analyse the impacts of mutations on membrane protein stability and the likelihood of them being disease associated. mCSM-membrane derives from our well-established mutation modelling approach that uses graph-based signatures to model protein geometry and physicochemical properties for supervised learning. Our stability predictor achieved correlations of up to 0.72 and 0.67 (on cross validation and blind tests, respectively), while our pathogenicity predictor achieved a Matthew's Correlation Coefficient (MCC) of up to 0.77 and 0.73, outperforming previously described methods in both predicting changes in stability and in identifying pathogenic variants. mCSM-membrane will be an invaluable and dedicated resource for investigating the effects of single-point mutations on membrane proteins through a freely available, user friendly web server at http://biosig.unimelb.edu.au/mcsm_membrane.

Highlights

Integral membrane proteins play an essential role as the gateway to the cell, mediating transport, signalling and adhesion amongst many other functions
Mutations in membrane proteins are associated with a wide variety of common diseases, including heart disease, and have been the site of action for over 50% of small molecule drugs [1]
The general workflow of mCSM-membrane is shown in Figure 1. mCSM-membrane was trained using two separate data sets of experimentally characterized mutations in transmembrane proteins, for which 3D structures were available

Summary

INTRODUCTION

Integral membrane proteins play an essential role as the gateway to the cell, mediating transport, signalling and adhesion amongst many other functions. Mutations in membrane proteins are associated with a wide variety of common diseases, including heart disease, and have been the site of action for over 50% of small molecule drugs [1]. While they represent 20–30% of the genes in the human genome [2,3,4], they can be challenging to experimentally characterise as they tend to be unstable when extracted from the lipid bilayer. Predictive performance of the molecular consequences of mutations in membrane proteins

MATERIALS AND METHODS

Method

Findings

CONCLUSION