Increased Aggregation Is More Frequently Associated to Human Disease-Associated Mutations Than to Neutral Polymorphisms

PLoS Computational Biology
Greet De BaetsJoost Schymkowitz

Abstract

Protein aggregation is a hallmark of over 30 human pathologies. In these diseases, the aggregation of one or a few specific proteins is often toxic, leading to cellular degeneration and/or organ disruption in addition to the loss-of-function resulting from protein misfolding. Although the pathophysiological consequences of these diseases are overt, the molecular dysregulations leading to aggregate toxicity are still unclear and appear to be diverse and multifactorial. The molecular mechanisms of protein aggregation and therefore the biophysical parameters favoring protein aggregation are better understood. Here we perform an in silico survey of the impact of human sequence variation on the aggregation propensity of human proteins. We find that disease-associated variations are statistically significantly enriched in mutations that increase the aggregation potential of human proteins when compared to neutral sequence variations. These findings suggest that protein aggregation might have a broader impact on human disease than generally assumed and that beyond loss-of-function, the aggregation of mutant proteins involved in cancer, immune disorders or inflammation could potentially further contribute to disease by additional burde...Continue Reading

References

Oct 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·D J SelkoeT Oltersdorf
Aug 16, 2000·Proceedings of the National Academy of Sciences of the United States of America·D E OtzenM Oliveberg
Apr 11, 2001·Human Mutation·Z Wang, J Moult
Jan 10, 2003·Nucleic Acids Research·John WestbrookHelen M Berman
Jun 21, 2003·Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences·Michele VendruscoloChristopher M Dobson
Aug 15, 2003·Nature·Fabrizio ChitiChristopher M Dobson
Dec 3, 2003·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·Lawreen Heller ConnorsCatherine E Costello
May 5, 2004·Proceedings of the National Academy of Sciences of the United States of America·Salvador VenturaLuis Serrano
Sep 14, 2004·Nature Biotechnology·Ana-Maria Fernandez-EscamillaLuis Serrano
Jun 28, 2005·Nucleic Acids Research·Joost SchymkowitzLuis Serrano
Sep 20, 2005·Journal of Molecular Biology·Peng YueJohn Moult
Nov 3, 2005·Proceedings of the National Academy of Sciences of the United States of America·Alexandra Esteras-ChopoManuela López de la Paz
Dec 20, 2005·Journal of Molecular Biology·Frederic RousseauJoost W H Schymkowitz
Jun 8, 2006·Annual Review of Biochemistry·Fabrizio Chiti, Christopher M Dobson
Sep 19, 2006·Quarterly Reviews of Biophysics·Hilal A Lashuel, Peter T Lansbury
Feb 28, 2007·BMC Bioinformatics·Oscar Conchillo-SoléSalvador Ventura
Jan 25, 2008·The EMBO Journal·Konstanze F WinklhoferChristian Haass
Feb 26, 2008·Current Opinion in Chemical Biology·Leila M LuheshiChristopher M Dobson
Jun 24, 2008·Chemical Society Reviews·Gian Gaetano Tartaglia, Michele Vendruscolo
May 6, 2009·Chembiochem : a European Journal of Chemical Biology·Alexander K BuellTuomas P J Knowles
Aug 22, 2009·PLoS Computational Biology·Joost Van DurmeJoost Schymkowitz
Aug 22, 2009·PLoS Computational Biology·Virginia Castillo, Salvador Ventura
Aug 27, 2009·Proceedings of the National Academy of Sciences of the United States of America·Anat Ben-ZviRichard I Morimoto
Aug 29, 2009·Mutation Research·Maria Chiara ScainiEmma D'Andrea
Mar 18, 2011·Human Mutation·Janita ThusbergMauno Vihinen
Mar 30, 2011·Nature Chemical Biology·Jie XuJoost Schymkowitz
Oct 13, 2011·Journal of Internal Medicine·P T SattianayagamJ D Gillmore
Nov 5, 2011·Nucleic Acids Research·Ivica LetunicPeer Bork
Nov 15, 2011·Nucleic Acids Research·Greet De BaetsFrederic Rousseau
Mar 20, 2012·Cell·David Eisenberg, Mathias Jucker
Mar 29, 2012·Proceedings of the National Academy of Sciences of the United States of America·Martin KurnikMikael Oliveberg
Jun 21, 2012·The Journal of Biological Chemistry·Ana P D Ano BomJerson L Silva
Jul 10, 2012·The Journal of Biological Chemistry·Aleksandra SiekierskaFrederic Rousseau
Nov 7, 2012·Nature·UNKNOWN 1000 Genomes Project ConsortiumGil A McVean
Nov 28, 2012·Frontiers in Genetics·Della C David

❮ Previous
Next ❯

Citations

Jan 20, 2016·Nature Chemical Biology·Joost Schymkowitz, Frederic Rousseau
Oct 1, 2016·Scientific Reports·Ricardo Sant'AnnaSalvador Ventura
Mar 7, 2017·Frontiers in Neuroscience·Esther StrooAlejandro Mata-Cabana
Jun 2, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Corey L AndersonTimothy J Kamp
Feb 19, 2021·Molecular and Cellular Biochemistry·Mohanad AhmadSanela Martic-Milne
Jul 6, 2021·Frontiers in Molecular Biosciences·Michele MontiGian Gaetano Tartaglia
Aug 9, 2021·International Journal of Biological Macromolecules·Sara La MannaDaniela Marasco
Dec 1, 2020·Journal of the American Chemical Society·Emma E CawoodAndrew J Wilson
Nov 1, 2017·Biochemistry·Wilfredo ColónKe Xia

❮ Previous
Next ❯

Software Mentioned

VariBench
YASARA
FoldX
TMHM
TANGO

Related Concepts

Related Feeds

Aging-Associated Metabolic Disorders

Age is associated with many metabolic disorders including cardiovascular diseases, type 2 diabetes, stroke and heart disease. The mediators in aging process have been suggested to play a part in the cellular processes responsible for these metabolic disorders. Here is the latest research on aging-associated metabolic disorders.

Alpha-Synuclein Aggregation

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.

Cancer -Omics

A variety of different high-throughput technologies can be used to identify the complete catalog of changes that characterize the molecular profile of cohorts of tumor samples. Discover the latest insights gained from cancer 'omics' in this feed.

ALS & FTD: TDP-43

TAR DNA-binding protein 43 (TDP-43) is a pathological protein identified in sporadic Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Here are the latest discoveries pertaining to TDP-43 and these diseases.

Alpha-Synuclein Structure & Function

α-Synuclein is an integral component of Lewy bodies which are comprised of protein clumps and are a pathological hallmark of Parkinson’s disease. Here is the latest research on α-synuclein structure and function.

Alpha-Synuclein Aggregation (MDS)

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.