Protein–Protein Interactions Mediated by Intrinsically Disordered Protein Regions Are Enriched in Missense Mutations
department or school: Other UBC
data provider: DSpace
identifier citation: Biomolecules 10 (8): 1097 (2020)
contributor: Michael Smith Laboratories
creator: Wong, Eric Tsz Chung
creator: So, Victor
creator: Guron, Mike
creator: Kuechler, Erich R.
creator: Malhis, Nawar
creator: Bui, Jennifer M.
creator: Gsponer, Jörg
issued: 2020-09-18T14:52:30Z
issued: 2020-07-24
description: Because proteins are fundamental to most biological processes, many genetic diseases can be traced back to single nucleotide variants (SNVs) that cause changes in protein sequences. However, not all SNVs that result in amino acid substitutions cause disease as each residue is under different structural and functional constraints. Influential studies have shown that protein–protein interaction interfaces are enriched in disease-associated SNVs and depleted in SNVs that are common in the general population. These studies focus primarily on folded (globular) protein domains and overlook the prevalent class of protein interactions mediated by intrinsically disordered regions (IDRs). Therefore, we investigated the enrichment patterns of missense mutation-causing SNVs that are associated with disease and cancer, as well as those present in the healthy population, in structures of IDR-mediated interactions with comparisons to classical globular interactions. When comparing the different categories of interaction interfaces, division of the interface regions into solvent-exposed rim residues and buried core residues reveal distinctive enrichment patterns for the various types of missense mutations. Most notably, we demonstrate a strong enrichment at the interface core of interacting IDRs in disease mutations and its depletion in neutral ones, which supports the view that the disruption of IDR interactions is a mechanism underlying many diseases. Intriguingly, we also found an asymmetry across the IDR interaction interface in the enrichment of certain missense mutation types, which may hint at an increased variant tolerance and urges further investigations of IDR interactions.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/76082
note: biomoleculesArticleProtein–Protein Interactions Mediated byIntrinsically Disordered Protein Regions AreEnriched in Missense MutationsEric T. C. Wong , Victor So, Mike Guron, Erich R. Kuechler, Nawar Malhis, Jennifer M. Buiand Jörg Gsponer *Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada;eric_wong@live.ca (E.T.C.W.); victor.kaiming.so@gmail.com (V.S.); mike_guron@alumni.ubc.ca (M.G.);erich.kuechler@gmail.com (E.R.K.); nmalhis@msl.ubc.ca (N.M.); jennbui@gmail.com (J.M.B.)* Correspondence: gsponer@msl.ubc.ca; Tel.: +1-604-827-4731Received: 13 June 2020; Accepted: 20 July 2020; Published: 24 July 2020Abstract: Because proteins are fundamental to most biological processes, many genetic diseasescan be traced back to single nucleotide variants (SNVs) that cause changes in protein sequences.However, not all SNVs that result in amino acid substitutions cause disease as each residue is underdifferent structural and functional constraints. Influential studies have shown that protein–proteininteraction interfaces are enriched in disease-associated SNVs and depleted in SNVs that are commonin the general population. These studies focus primarily on folded (globular) protein domains andoverlook the prevalent class of protein interactions mediated by intrinsically disordered regions(IDRs). Therefore, we investigated the enrichment patterns of missense mutation-causing SNVs thatare associated with disease and cancer, as well as those present in the healthy population, in structuresof IDR-mediated interactions with comparisons to classical globular interactions. When comparingthe different categories of interaction interfaces, division of the interface regions into solvent-exposedrim residues and buried core residues reveal distinctive enrichment patterns for the various typesof missense mutations. Most notably, we demonstrate a strong enrichment at the interface core ofinteracting IDRs in disease mutations and its depletion in neutral ones, …
has type: Article
is shown at: 10.14288/1.0394424
language: eng
peer review status: Reviewed
provider: Vancouver : University of British Columbia Library
publisher: Multidisciplinary Digital Publishing Institute
publisher DOI: 10.3390/biom10081097
rights: CC BY 4.0
rights URI: https://creativecommons.org/licenses/by/4.0/
scholar level: Faculty
scholar level: Researcher
subject: intrinsically disordered proteins
subject: single nucleotide variants
subject: protein–protein interactions
subject: interface core and rim
subject: human disease
type: Text
identifier URI: http://hdl.handle.net/2429/76082