Cited by 35Genomics and Rare DiseasesProtein Structure and DynamicsMachine Learning in Bioinformatics

Interpreting the molecular mechanisms of disease variants in human transmembrane proteins

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Tiemann, Johanna Katarina Sofie, Zschach, Henrike, Lindorff-Larsen, Kresten, Stein, Amelie·2023·Biophysical Journal

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Abstract

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.

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Authors
Tiemann, J. K. S., Zschach, H., Lindorff-Larsen, K., & Stein, A.
Affiliations
University of Copenhagen (DK)
Corresponding author
Stein, Amelie
Venue
Biophysical Journal
Publisher
Elsevier BV
Published
2023-06
Volume
122
Issue
11
Pages
2176-2191
ISSN
0006-3495 (ISSN-L)
OpenAlex
W4313530868
Cited by
35
References
92
Citations by year
2026: 5 · 2025: 12 · 2024: 6 · 2023: 8 · 2022: 3 · 2012: 1
FWCI
5.15
Type
journal article
Language
en
Open access
Locations
  • Biophysical Journal (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
Funders
  • Lundbeck Foundation (R272-2017-4528)
  • Novo Nordisk Fonden (NNF18OC0033950)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
Keywords
missense mutations, transmembrane proteins, membrane proteins, pathogenic variants, thermodynamic stability, sequence conservation, protein evolution, variant pathogenicity prediction, human proteome
MeSH terms
Humans, Membrane Proteins, Signal Transduction, Mutation, Missense

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