Three-dimensional reconstruction of protein networks provides insight into human genetic disease
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Open Access
- 15 January 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Biotechnology
- Vol. 30 (2), 159-164
- https://doi.org/10.1038/nbt.2106
Abstract
Large-scale structural genomics and genome-wide association studies generate a wealth of data relevant to human disease. Wang et al. interpret these data in the context of a protein interaction network, showing that systematic analyses of the structural interfaces hit by mutations yield insights into pathogenesis. To better understand the molecular mechanisms and genetic basis of human disease, we systematically examine relationships between 3,949 genes, 62,663 mutations and 3,453 associated disorders by generating a three-dimensional, structurally resolved human interactome. This network consists of 4,222 high-quality binary protein-protein interactions with their atomic-resolution interfaces. We find that in-frame mutations (missense point mutations and in-frame insertions and deletions) are enriched on the interaction interfaces of proteins associated with the corresponding disorders, and that the disease specificity for different mutations of the same gene can be explained by their location within an interface. We also predict 292 candidate genes for 694 unknown disease-to-gene associations with proposed molecular mechanism hypotheses. This work indicates that knowledge of how in-frame disease mutations alter specific interactions is critical to understanding pathogenesis. Structurally resolved interaction networks should be valuable tools for interpreting the wealth of data being generated by large-scale structural genomics and disease association studies.Keywords
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