title: Elucidating common structural features of human pathogenic variations using large-scale atomic-resolution protein networks.
abstract: With the rapid growth of structural genomics, numerous protein crystal structures have become available. However, the parallel increase in knowledge of the functional principles underlying biological processes, and more specifically the underlying molecular mechanisms of disease, has been less dramatic. This notwithstanding, the study of complex cellular networks has made possible the inference of protein functions on a large scale. Here, we combine the scale of network systems biology with the resolution of traditional structural biology to generate a large-scale atomic-resolution interactome-network comprising 3,398 interactions between 2,890 proteins with a well-defined interaction interface and interface residues for each interaction. Within the framework of this atomic-resolution network, we have explored the structural principles underlying variations causing human-inherited disease. We find that in-frame pathogenic variations are enriched at both the interface and in the interacting domain, suggesting that variations not only at interface "hot-spots," but in the entire interacting domain can result in alterations of interactions. Further, the sites of pathogenic variations are closely related to the biophysical strength of the interactions they perturb. Finally, we show that biochemical alterations consequent to these variations are considerably more disruptive than evolutionary changes, with the most significant alterations at the protein interaction interface.
authors.affiliation: Department 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.
authors.forename: Jishnu
authors.initials: J
authors.lastname: Das
authors.forename: Hao Ran
authors.initials: HR
authors.lastname: Lee
authors.forename: Adithya
authors.initials: A
authors.lastname: Sagar
authors.forename: Robert
authors.initials: R
authors.lastname: Fragoza
authors.forename: Jin
authors.initials: J
authors.lastname: Liang
authors.forename: Xiaomu
authors.initials: X
authors.lastname: Wei
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Wang
authors.forename: Matthew
authors.initials: M
authors.lastname: Mort
authors.forename: Peter D
authors.initials: PD
authors.lastname: Stenson
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Yu
mesh_terms: D019295:Computational Biology; D030562:Databases, Protein; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000473:pathology; D006801:Humans; D008962:Models, Theoretical; D060066:Protein Interaction Maps / Q000235:genetics*; D013329:Structure-Activity Relationship; D049490:Systems Biology
keywords: network systems biology; pathogenic variations; protein-protein interactions; structural biology