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In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
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Elucidating common structural features of human pathogenic variations using large-scale atomic-resolution protein
Jishnu Das1, Hao Ran Lee, Adithya Sagar
1Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, 14853; Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, 14853.
Human Mutation
|March 7, 2014
Summary
This study integrates network and structural biology to map protein interactions at atomic resolution. Pathogenic variations disrupting these interactions are linked to human diseases, highlighting the importance of protein interface analysis.
Area of Science:
- Structural biology
- Systems biology
- Genomics
Background:
- Growing protein structural data contrasts with limited understanding of disease mechanisms.
- Large-scale protein function inference is possible through cellular network studies.
Purpose of the Study:
- To create a large-scale, atomic-resolution interactome network.
- To investigate structural principles of human-inherited disease variations.
Main Methods:
- Combining network systems biology with structural biology.
- Generating an atomic-resolution interactome network of 3,398 interactions.
- Analyzing protein interaction interfaces and interface residues.
Main Results:
- Identified 3,398 protein interactions with defined interfaces.
- Found pathogenic variations enriched at interaction interfaces and domains.
- Linked variation sites to the biophysical strength of perturbed interactions.
Conclusions:
- Variations in entire interacting domains, not just hotspots, can alter protein interactions.
- Biochemical alterations from variations are more disruptive than evolutionary changes.
- Protein interaction interfaces are critical sites for disease-related alterations.
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