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Role of Hsp70 ATPase domain intrinsic dynamics and sequence evolution in enabling its functional interactions with NEFs

Liu, Y and Gierasch, LM and Bahar, I (2010) Role of Hsp70 ATPase domain intrinsic dynamics and sequence evolution in enabling its functional interactions with NEFs. PLoS Computational Biology, 6 (9). ISSN 1553-734X

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Catalysis of ADP-ATP exchange by nucleotide exchange factors (NEFs) is central to the activity of Hsp70 molecular chaperones. Yet, the mechanism of interaction of this family of chaperones with NEFs is not well understood in the context of the sequence evolution and structural dynamics of Hsp70 ATPase domains. We studied the interactions of Hsp70 ATPase domains with four different NEFs on the basis of the evolutionary trace and co-evolution of the ATPase domain sequence, combined with elastic network modeling of the collective dynamics of the complexes. Our study reveals a subtle balance between the intrinsic (to the ATPase domain) and specific (to interactions with NEFs) mechanisms shared by the four complexes. Two classes of key residues are distinguished in the Hsp70 ATPase domain: (i) highly conserved residues, involved in nucleotide binding, which mediate, via a global hinge-bending, the ATPase domain opening irrespective of NEF binding, and (ii) not-conserved but co-evolved and highly mobile residues, engaged in specific interactions with NEFs (e.g., N57, R258, R262, E283, D285). The observed interplay between these respective intrinsic (pre-existing, structure-encoded) and specific (co-evolved, sequence-dependent) interactions provides us with insights into the allosteric dynamics and functional evolution of the modular Hsp70 ATPase domain. © 2010 Liu et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Liu, Yyil43@pitt.eduYIL43
Gierasch, LM
Bahar, Iivet.bahar@stonybrook.eduBAHAR
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 September 2010
Date Type: Publication
Journal or Publication Title: PLoS Computational Biology
Volume: 6
Number: 9
DOI or Unique Handle: 10.1371/journal.pcbi.1000931
Schools and Programs: School of Medicine > Computational Biology
Refereed: Yes
ISSN: 1553-734X
MeSH Headings: Adenosine Triphosphatases--chemistry; Adenosine Triphosphatases--genetics; Adenosine Triphosphatases--metabolism; Amino Acid Sequence; Animals; Binding Sites; Cattle; Computational Biology; Escherichia coli Proteins--chemistry; Escherichia coli Proteins--genetics; Escherichia coli Proteins--metabolism; Evolution, Molecular; HSP70 Heat-Shock Proteins--chemistry; HSP70 Heat-Shock Proteins--genetics; HSP70 Heat-Shock Proteins--metabolism; Humans; Molecular Chaperones--chemistry; Molecular Chaperones--genetics; Molecular Chaperones--metabolism; Molecular Dynamics Simulation; Multiprotein Complexes; Normal Distribution; Phylogeny; Protein Structure, Tertiary; Sequence Alignment
Other ID: NLM PMC2940730
PubMed Central ID: PMC2940730
PubMed ID: 20862304
Date Deposited: 15 Aug 2012 17:55
Last Modified: 17 Mar 2023 11:55


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