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A Protocol for Computer-Based Protein Structure and Function Prediction
Published on: November 3, 2011
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Functional characterization of 3D protein structures informed by human genetic diversity
Michael Hicks1, Istvan Bartha2, Julia di Iulio3
1Human Longevity, Inc., San Diego, CA 92121.
Summary
Analyzing human genetic variation in 3D protein structures reveals functional sites. Sixty percent of proteins have intolerant sites, aiding in understanding protein function and disease. This study defines functional 3D sites across the proteome.
Area of Science:
- Genomics
- Structural Biology
- Bioinformatics
Background:
- Human genetic variation data offers insights into protein structure and function.
- Understanding 3D protein structure is crucial for deciphering biological mechanisms.
Purpose of the Study:
- To analyze 3D positional conservation in human proteins using large-scale genetic variation data.
- To identify and define functional 3D sites within protein structures proteome-wide.
Main Methods:
- Utilized genetic variant data from nearly 140,000 individuals.
- Analyzed 3D positional conservation across 4,715 proteins and 3,951 homology models.
- Examined missense and synonymous variants to identify structurally intolerant sites.
Main Results:
- Sixty percent of protein structures contain at least one intolerant 3D site.
- Structural intolerance data correlated with deep and shallow mutational scanning functional readouts.
- Analysis revealed distinct features for ligand binding pockets and orthosteric/allosteric sites.
Conclusions:
- Large-scale human genetic variation data enables proteome-wide definition of functional 3D sites.
- This approach provides a robust method for identifying functionally critical regions in proteins.
- Findings contribute to a deeper understanding of protein function, evolution, and disease association.
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