4.7 Article

Molecular dynamics simulations of Hsp40 J-domain mutants identifies disruption of the critical HPD-motif as the key factor for impaired curing in vivo of the yeast prion [URE3]

Journal

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 36, Issue 7, Pages 1764-1775

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2017.1334594

Keywords

heat shock protein; MD simulation; conformational change; molecular docking; Hsp40-Hsp70 interaction

Funding

  1. National Natural Science Foundation of China [31570154, 31201285]
  2. Intramural Research Program of the NIH
  3. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  4. Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry of China [2013693]
  5. Education Department of Liaoning Province, China [L2014009]

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Genetic screens using Saccharomyces cerevisiae have identified an array of Hsp40 (Ydj1p) J-domain mutants that are impaired in the ability to cure the yeast [URE3] prion through disrupting functional interactions with Hsp70. However, biochemical analysis of some of these Hsp40J-domain mutants has so far failed to provide major insight into the specific functional changes in Hsp40-Hsp70 interactions. To explore the detailed structural and dynamic properties of the Hsp40J-domain, 20 ns molecular dynamic simulations of 4 mutants (D9A, D36A, A30T, and F45S) and wild-type J-domain were performed, followed by Hsp70 docking simulations. Results demonstrated that although the Hsp70 interaction mechanism of the mutants may vary, the major structural change was targeted to the critical HPD motif of the J-domain. Our computational analysis fits well with previous yeast genetics studies regarding highlighting the importance of J-domain function in prion propagation. During the molecular dynamics simulations several important residues were identified and predicted to play an essential role in J-domain structure. Among these residues, Y26 and F45 were confirmed, using both in silico and in vivo methods, as being critical for Ydj1p function.

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