ArticleProceedings of the National Academy of Sciences of the United States of America2016
Interplay between hydrophobicity and the positive-inside rule in determining membrane-protein topology.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed, 51 citations in OpenAlex.
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- Insights into the inner workings of transformer models for protein function prediction.Bioinformatics (Oxford, England) · 2024Article
- The pathogen-encoded signalling receptor Tir exploits host-like intrinsic disorder for infection.Communications biology · 2024Article
- Computational design of BclxL inhibitors that target transmembrane domain interactions.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Exopolysaccharide Biosynthesis inInternational journal of molecular sciences · 2023Article
- Spf1 and Ste24: quality controllers of transmembrane protein topology in the eukaryotic cell.Frontiers in cell and developmental biology · 2023Review
- mPPases create a conserved anionic membrane fingerprint as identified via multi-scale simulations.PLoS computational biology · 2022Article
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- Improving the topology prediction of α-helical transmembrane proteins with deep transfer learning.Computational and structural biotechnology journal · 2022Article
- The Molecular Biodiversity of Protein Targeting and Protein Transport Related to the Endoplasmic Reticulum.International journal of molecular sciences · 2021Review
- Structure-based insights into evolution of rhodopsins.Communications biology · 2021Article
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- Inducible intracellular membranes: molecular aspects and emerging applications.Microbial cell factories · 2020Review
- Article
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4 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The energetics of membrane-protein interactions determine protein topology and structure: hydrophobicity drives the insertion of helical segments into the membrane, and positive charges orient the protein with respect to the membrane plane according to the positive-inside rule. Until recently, however, quantifying these contributions met with difficulty, precluding systematic analysis of the energetic basis for membrane-protein topology. We recently developed the dsTβL method, which uses deep sequencing and in vitro selection of segments inserted into the bacterial plasma membrane to infer insertion-energy profiles for each amino acid residue across the membrane, and quantified the insertion contribution from hydrophobicity and the positive-inside rule. Here, we present a topology-prediction algorithm called TopGraph, which is based on a sequence search for minimum dsTβL insertion energy. Whereas the average insertion energy assigned by previous experimental scales was positive (unfavorable), the average assigned by TopGraph in a nonredundant set is -6.9 kcal/mol. By quantifying contributions from both hydrophobicity and the positive-inside rule we further find that in about half of large membrane proteins polar segments are inserted into the membrane to position more positive charges in the cytoplasm, suggesting an interplay between these two energy contributions. Because membrane-embedded polar residues are crucial for substrate binding and conformational change, the results implicate the positive-inside rule in determining the architectures of membrane-protein functional sites. This insight may aid structure prediction, engineering, and design of membrane proteins. TopGraph is available online (topgraph.weizmann.ac.il).
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