Three-dimensional reconstruction of protein networks provides insight into human genetic disease

By Xiujuan Wang, Xiaomu Wei, Bram Thijssen, Jishnu Das, Steven M. Lipkin, Haiyuan Yu. Nature Biotechnology, 2012

381 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2c813935f8a0e814900b3c39be7d7467a274844c

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Citations in the corpus

Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive review (2012, methodology): “…been described in Sections 2.3.4, 2.5.2 and 2.5.3 (Xiong & Choe, 2008; Antal et al., 2009; Kitsak et al., 2010; Luni et al., 2010; Farkas et al., 2011; Liu et al., 2011, 2012; Banerjee & Roy, 2012; Cowan et al., 2012; Mones et al., 2012; Nepusz & Vicsek, 2012; Valente, 2012; Wang et al., 2012a).”
Towards a structurally resolved human protein interaction network (2021, methodology): “The structural characterization of protein complexes is a critical step in understanding the mechanisms of protein function, and in studying the impact of mutations 4,6–8 and the regulation of cellular processes via the post-translational tuning of binding affinities 9–12 .”
The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine (2013, positive): “Finally, HGMD has been used as a resource for structural biologists in the reconstruction of protein interaction networks (Wang et al. 2012; Guo et al. 2013).”
Interactome3D: adding structural details to protein networks (2013, background): “Indeed, knowledge of the molecular details of binding has permitted a more rational analysis of exposed disease-causing mutations 6,7 ; the design of experiments to disrupt an interaction and perturb systems where interactions are involved 8 ; and distinction between ‘singlish’ and multi-interface…”
HINT: High-quality protein interactomes and their applications in understanding human disease (2012, background): “We show in a recent study that the pathogenesis of human disease can be better understood by looking at the position of mutations on interaction interfaces [36].”
A proteome-wide fission yeast interactome reveals network evolution principles from yeasts to human (2016, background): “Thus, these sites are critical to protein binding and subsequent function, and changes at these sites alter protein interactions in a manner analogous to a single amino acid change disrupting protein interactions in human disease (Wang et al., 2012; Wei et al., 2014).”
Computational approaches in target identification and drug discovery (2016, background): “Another recent network-based applicationwas the integrationof large-scale structural genomics anddisease association studies, to generate three-dimensional human interactome, that resulted in the identification of candidate genes for unknown disease-to-gene associations with proposed molecular mecha”
The scoring of poses in protein-protein docking: current capabilities and future directions (2013, background): “The atomic-resolution annotation of protein interaction networks can give insights into the kinetics [1-5], thermodynamics [6-10] and organisation [11-13] of the complex systems they constitute, as well as human disease [14,15].”
Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics (2013, methodology): “To further corroborate this, we tested a specific case, the Wiskott-Aldrich syndrome protein (WASP), using yeast two-hybrid (Y2H) experiments (32).”