TY - JOUR

T1 - Interpreting the molecular mechanisms of disease variants in human transmembrane proteins

AU - Tiemann, Johanna Katarina Sofie

AU - Zschach, Henrike

AU - Lindorff-Larsen, Kresten

AU - Stein, Amelie

N1 - Publisher Copyright: © 2023 Biophysical Society

PY - 2023

Y1 - 2023

N2 - Next-generation sequencing of human genomes reveals millions of missense variants, some of which may lead to loss of protein function and ultimately disease. Here, we investigate missense variants in membrane proteins—key drivers in cell signaling and recognition. We find enrichment of pathogenic variants in the transmembrane region across 19,000 functionally classified variants in human membrane proteins. To accurately predict variant consequences, one fundamentally needs to understand the underlying molecular processes. A key mechanism underlying pathogenicity in missense variants of soluble proteins has been shown to be loss of stability. Membrane proteins, however, are widely understudied. Here, we interpret variant effects on a larger scale by performing structure-based estimations of changes in thermodynamic stability using a membrane-specific energy function and analyses of sequence conservation during evolution of 15 transmembrane proteins. We find evidence for loss of stability being the cause of pathogenicity in more than half of the pathogenic variants, indicating that this is a driving factor also in membrane-protein-associated diseases. Our findings show how computational tools aid in gaining mechanistic insights into variant consequences for membrane proteins. To enable broader analyses of disease-related and population variants, we include variant mappings for the entire human proteome.

AB - Next-generation sequencing of human genomes reveals millions of missense variants, some of which may lead to loss of protein function and ultimately disease. Here, we investigate missense variants in membrane proteins—key drivers in cell signaling and recognition. We find enrichment of pathogenic variants in the transmembrane region across 19,000 functionally classified variants in human membrane proteins. To accurately predict variant consequences, one fundamentally needs to understand the underlying molecular processes. A key mechanism underlying pathogenicity in missense variants of soluble proteins has been shown to be loss of stability. Membrane proteins, however, are widely understudied. Here, we interpret variant effects on a larger scale by performing structure-based estimations of changes in thermodynamic stability using a membrane-specific energy function and analyses of sequence conservation during evolution of 15 transmembrane proteins. We find evidence for loss of stability being the cause of pathogenicity in more than half of the pathogenic variants, indicating that this is a driving factor also in membrane-protein-associated diseases. Our findings show how computational tools aid in gaining mechanistic insights into variant consequences for membrane proteins. To enable broader analyses of disease-related and population variants, we include variant mappings for the entire human proteome.

U2 - 10.1016/j.bpj.2022.12.031

DO - 10.1016/j.bpj.2022.12.031

M3 - Journal article

C2 - 36600598

AN - SCOPUS:85147594140

VL - 122

JO - Biophysical Society. Annual Meeting. Abstracts

JF - Biophysical Society. Annual Meeting. Abstracts

SN - 0523-6800

IS - 11

ER -