An exhaustive analysis of single amino acid variants in helical transmembrane proteins

Abstract

Single nucleotide variants (SNVs) have been widely studied in the past due to being the main source of human genetic variation. Less is known about the effect of single amino acid variants (SAVs) due to the immense resources required for comprehensive experimental studies. In contrast, in silico methods predicting the effects of sequence variants upon molecular function and upon the organism are readily available and have contributed unexpected suggestions, e.g. that SAVs common to a human population (shared by >5% of the population) have, on average, more significant impact on the molecular function of proteins than do rare SAVs (shared by <1% of the population). Here, we investigated the impact of variants in a human population upon helical transmembrane proteins (TMPs). Three main results stood out. Firstly, common SAVs, on average, have stronger effects than rare SAVs for TMPs, and are enriched, in particular, in the membrane helices. Secondly, proteins with seven transmembrane helices (7TM, including GPCRs, i.e. G protein-coupled receptors) are depleted of SAVs in comparison to other proteins, possibly due to increased evolutionary constraints in these important proteins. Thirdly, rare SAVs with strong effect are significantly absent (over common SAVs) in signal peptide regions. Key words: helical transmembrane proteins, single amino acid variants, functional features prediction, human proteome, topology prediction.Abbreviations used: GPCR, G protein-coupled receptors (7-pass TMPs); non-TMP, nontransmembrane proteins (due to dedication errors, these may include some beta-barrel membrane proteins); SAV, single amino acid variant; SNV, single nucleotide variant; TMH, transmembrane helix; TMP, transmembrane protein.

Protein–protein and protein-nucleic acid binding residues important for common and rare sequence variants in human

“…Predicting the effect of SAVs on molecular protein function for the ExAC data set of 60,706 exosomes [5], it has been shown that a higher fraction of all common than of all rare SAVs affect molecular protein function [1]. One possible explanation is that proteins function differently in sub-populations; an example for this are G-coupled receptors (GPCR) [13] (in fact, all proteins with seven transmembrane helices such as GPCRs stand out in the difference of effect between common and rare SAVs [14]).…”