Protein Destabilization as a Common Factor in Diverse Inherited Disorders

Rachel L. Redler, Jhuma Das, Juan R. Diaz, Nikolay Dokholyan

Research output: Contribution to journalLetter

15 Citations (Scopus)

Abstract

Protein destabilization by amino acid substitutions is proposed to play a prominent role in widespread inherited human disorders, not just those known to involve protein misfolding and aggregation. To test this hypothesis, we computationally evaluate the effects on protein stability of all possible amino acid substitutions in 20 disease-associated proteins with multiple identified pathogenic missense mutations. For 18 of the 20 proteins studied, substitutions at known positions of pathogenic mutations are significantly more likely to destabilize the native protein fold (as indicated by more positive values of ∆∆G). Thus, positions identified as sites of disease-associated mutations, as opposed to non-disease-associated sites, are predicted to be more vulnerable to protein destabilization upon amino acid substitution. This finding supports the notion that destabilization of native protein structure underlies the pathogenicity of broad set of missense mutations, even in cases where reduced protein stability and/or aggregation are not characteristic of the disease state.

Original languageEnglish (US)
Pages (from-to)11-16
Number of pages6
JournalJournal Of Molecular Evolution
Volume82
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

genetic disorders
protein
Amino Acid Substitution
Proteins
amino acid substitution
proteins
mutation
substitution
Protein Stability
missense mutation
Missense Mutation
amino acid
Mutation
protein structure
Virulence
pathogenicity
fold

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics

Cite this

Redler, Rachel L. ; Das, Jhuma ; Diaz, Juan R. ; Dokholyan, Nikolay. / Protein Destabilization as a Common Factor in Diverse Inherited Disorders. In: Journal Of Molecular Evolution. 2016 ; Vol. 82, No. 1. pp. 11-16.
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Protein Destabilization as a Common Factor in Diverse Inherited Disorders. / Redler, Rachel L.; Das, Jhuma; Diaz, Juan R.; Dokholyan, Nikolay.

In: Journal Of Molecular Evolution, Vol. 82, No. 1, 01.01.2016, p. 11-16.

Research output: Contribution to journalLetter

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