Role of Hsp70 ATPase Domain Intrinsic Dynamics and Sequence Evolution in Enabling its Functional Interactions with NEFs

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.

• Publication year

  2010

• Venue

  PLoS Comput. Biol.

• Publication date

  2010-09-01

• Fields of study

  Biology, Materials Science, Chemistry, Computer Science, Medicine

• Identifiers
  DOI 10.1371/journal.pcbi.1000931PMID 20862304PMCID 2940730
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Protein data bank

  2012influential reference
• The Pfam protein families database

  2011influential reference
• Global dynamics of proteins: bridging between structure and function.

  2010cited by this paper
• An interdomain sector mediating allostery in Hsp70 molecular chaperones

  2010cited by this paper
• Toward Understanding Allosteric Signaling Mechanisms in the ATPase Domain of Molecular Chaperones

  2010influential reference
• Sending Signals Dynamically

  2009cited by this paper
• Structural and functional diversity among eukaryotic Hsp70 nucleotide exchange factors.

  2009cited by this paper
• Allostery in Hsp70 chaperones is transduced by subdomain rotations.

  2009cited by this paper
• The intrinsic dynamics of enzymes plays a dominant role in determining the structural changes induced upon inhibitor binding

  2009cited by this paper
• Converging concepts of protein folding in vitro and in vivo

  2009cited by this paper
• Protein sectors: evolutionary units of three-dimensional structure.

  2009cited by this paper
• Protein Dynamism and Evolvability

  2009cited by this paper
• Linking folding and binding.

  2009cited by this paper
• Allosteric Transitions of Supramolecular Systems Explored by Network Models: Application to Chaperonin GroEL

  2009cited by this paper
• Structure of the Hsp110:Hsc70 nucleotide exchange machine.

  2008cited by this paper
• Hsp110 Is a Nucleotide-activated Exchange Factor for Hsp70*

  2008influential reference
• Intrinsically disordered proteins in human diseases: introducing the D2 concept.

  2008cited by this paper
• The structure of CCT–Hsc70NBD suggests a mechanism for Hsp70 delivery of substrates to the chaperonin

  2008cited by this paper
• Recognition Dynamics Up to Microseconds Revealed from an RDC-Derived Ubiquitin Ensemble in Solution

  2008cited by this paper
• Structural basis for the cooperation of Hsp70 and Hsp110 chaperones in protein folding.

  2008cited by this paper
• Compensating Enthalpic and Entropic Changes Hinder Binding Affinity Optimization

  2007cited by this paper
• Intrinsic dynamics of enzymes in the unbound state and relation to allosteric regulation.

  2007cited by this paper
• The Pfam protein families database

  2007cited by this paper
• Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker.

  2007cited by this paper
• Intrinsic motions along an enzymatic reaction trajectory

  2007cited by this paper
• Structural basis of J cochaperone binding and regulation of Hsp70.

  2007cited by this paper
• Allosteric regulation of Hsp70 chaperones by a proline switch.

  2006influential reference
• Residues crucial for maintaining short paths in network communication mediate signaling in proteins

  2006cited by this paper
• The diverse roles of J-proteins, the obligate Hsp70 co-chaperone.

  2006cited by this paper
• Anisotropic network model: systematic evaluation and a new web interface

  2006influential reference
• oGNM: online computation of structural dynamics using the Gaussian Network Model

  2006influential reference
• The changing landscape of protein allostery.

  2006cited by this paper
• Allosteric Regulation of Hsp70 Chaperones Involves a Conserved Interdomain Linker*

  2006cited by this paper
• Structural Genomics

  2005cited by this paper
• Structural changes involved in protein binding correlate with intrinsic motions of proteins in the unbound state.

  2005cited by this paper
• Using information theory to search for co-evolving residues in proteins

  2005cited by this paper
• Hsp70 chaperones: Cellular functions and molecular mechanism

  2005cited by this paper
• Regulation of Hsp70 function by HspBP1: structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange.

  2005cited by this paper
• Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes.

  2005cited by this paper
• Detection and reduction of evolutionary noise in correlated mutation analysis.

  2005cited by this paper
• Pathways of chaperone-mediated protein folding in the cytosol

  2004cited by this paper
• Small‐world network approach to identify key residues in protein–protein interaction

  2004cited by this paper
• An accurate, sensitive, and scalable method to identify functional sites in protein structures.

  2003cited by this paper
• BAG-1—a nucleotide exchange factor of Hsc70 with multiple cellular functions

  2003influential reference
• Covariation of amino acid positions in HIV-1 protease.

  2003cited by this paper
• Antibody Multispecificity Mediated by Conformational Diversity

  2003cited by this paper
• HspBP1, an Hsp70 Cochaperone, Has Two Structural Domains and Is Capable of Altering the Conformation of the Hsp70 ATPase Domain*

  2003influential reference
• Molecular Chaperones in the Cytosol: from Nascent Chain to Folded Protein

  2002cited by this paper
• Evolutionary predictions of binding surfaces and interactions.

  2002cited by this paper
• Structural clusters of evolutionary trace residues are statistically significant and common in proteins.

  2002cited by this paper
• Structure of a Bag/Hsc70 Complex: Convergent Functional Evolution of Hsp70 Nucleotide Exchange Factors

  2001influential reference
• Anisotropy of fluctuation dynamics of proteins with an elastic network model.

  2001influential reference
• Tuning of chaperone activity of Hsp70 proteins by modulation of nucleotide exchange

  2001cited by this paper
• Correlations among amino acid sites in bHLH protein domains: an information theoretic analysis.

  2000cited by this paper
• Evolutionary trace analysis of TGF-beta and related growth factors: implications for site-directed mutagenesis.

  2000cited by this paper
• Structural stability of binding sites: Consequences for binding affinity and allosteric effects

  2000cited by this paper
• The Protein Data Bank

  2000cited by this paper
• Analysis of heregulin symmetry by weighted evolutionary tracing.

  1999cited by this paper
• Evolutionarily conserved pathways of energetic connectivity in protein families.

  1999cited by this paper
• Effective use of sequence correlation and conservation in fold recognition.

  1999cited by this paper
• The Hsp70 and Hsp60 chaperone machines.

  1998cited by this paper
• Human Hsp70 molecular chaperone binds two calcium ions within the ATPase domain.

  1997cited by this paper
• Evolution of genetic redundancy

  1997cited by this paper
• Crystal structure of the nucleotide exchange factor GrpE bound to the ATPase domain of the molecular chaperone DnaK.

  1997cited by this paper
• Direct evaluation of thermal fluctuations in proteins using a single-parameter harmonic potential.

  1997influential reference
• An evolutionary trace method defines binding surfaces common to protein families.

  1996cited by this paper
• How Potassium Affects the Activity of the Molecular Chaperone Hsc70

  1995influential reference
• How Potassium Affects the Activity of the Molecular Chaperone Hsc70

  1995cited by this paper
• Covariation of residues in the homeodomain sequence family

  1995cited by this paper
• Can three-dimensional contacts in protein structures be predicted by analysis of correlated mutations?

  1994cited by this paper
• Correlated mutations and residue contacts in proteins

  1994cited by this paper
• Protein sequence alignments: a strategy for the hierarchical analysis of residue conservation

  1993cited by this paper
• An ATPase domain common to prokaryotic cell cycle proteins, sugar kinases, actin, and hsp70 heat shock proteins.

  1992cited by this paper
• Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein

  1990cited by this paper
• Identification of common molecular subsequences.

  1981cited by this paper
• A solution for the best rotation to relate two sets of vectors

  1976cited by this paper

• Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2

  2025cites this paper
• Radiation-induced effect of heat shock protein and potential clinical application

  2024cites this paper
• Heat Shock Proteins and Cancer: The FoxM1 Connection.

  2023cites this paper
• New insights into the structure and function of the complex between the Escherichia coli Hsp70, DnaK, and its nucleotide-exchange factor, GrpE

  2023cites this paper
• Distinct dynamical features of plasmodial and human HSP70-HSP110 highlight the divergence in their chaperone-assisted protein folding.

  2023cites this paper
• Lysine Trimethylation in Planktonic and Pellicle Modes of Growth in Acinetobacter baumannii.

  2023cites this paper
• Nucleotide Exchange Factors for Hsp70 Molecular Chaperones: GrpE, Hsp110/Grp170, HspBP1/Sil1, and BAG Domain Proteins.

  2023cites this paper
• Heat Shock Proteins in Benign Prostatic Hyperplasia and Prostate Cancer

  2022cites this paper
• Comparison of allosteric signaling in DnaK and BiP using mutual information between simulated residue conformations

  2022cites this paper
• Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets

  2022cites this paper
• Leveraging Protein Dynamics to Identify Functional Phosphorylation Sites using Deep Learning Models

  2022cites this paper
• Allosteric Inter-Domain Contacts in Bacterial Hsp70 Are Located in Regions That Avoid Insertion and Deletion Events

  2022cites this paper
• Evodiamine inhibits both stem cell and non-stem-cell populations in human cancer cells by targeting heat shock protein 70

  2021cites this paper
• Autophagic Inhibition via Lysosomal Integrity Dysfunction Leads to Antitumor Activity in Glioma Treatment

  2020cites this paper
• Identification of inhibitor binding hotspots in Acinetobacter baumannii β-ketoacyl acyl carrier protein synthase III using molecular dynamics simulation.

  2020cites this paper
• The Role of Conformational Dynamics and Allostery in Modulating Protein Evolution.

  2020cites this paper
• Dynamic View of Allosteric Regulation in the Hsp70 Chaperones by J-Domain Cochaperone and Post-Translational Modifications: Computational Analysis of Hsp70 Mechanisms by Exploring Conformational Landscapes and Residue Interaction Networks

  2020cites this paper
• Allostery and Structural Dynamics in Protein Evolution

  2019cites this paper
• Integration of network models and evolutionary analysis into high-throughput modeling of protein dynamics and allosteric regulation: theory, tools and applications

  2019cites this paper
• HspBP1 and anti‐HspBP1 levels in the serum of HIV‐infected individuals are associated to the disease progression

  2019cites this paper
• Discorhabdin N, a South African Natural Compound, for Hsp72 and Hsc70 Allosteric Modulation: Combined Study of Molecular Modeling and Dynamic Residue Network Analysis

  2019cites this paper
• An Active, Ligand-Responsive Pulling Geometry Reports on Internal Signaling between Subdomains of the DnaK Nucleotide-Binding Domain in Single-Molecule Mechanical Experiments.

  2019cites this paper
• Structural characterization and molecular dynamics simulations of the caprine and bovine solute carrier family 11 A1 (SLC11A1)

  2018cites this paper
• Allosteric Modulators of HSP90 and HSP70: Dynamics Meets Function through Structure-Based Drug Design.

  2018cites this paper
• Disrupted Hydrogen-Bond Network and Impaired ATPase Activity in an Hsc70 Cysteine Mutant.

  2018cites this paper
• Deciphering the role of dimer interface in intrinsic dynamics and allosteric pathways underlying the functional transformation of DNMT3A.

  2018cites this paper
• A Local Allosteric Network in Heat Shock Protein 70 (Hsp70) Links Inhibitor Binding to Enzyme Activity and Distal Protein-Protein Interactions.

  2018cites this paper
• ANALYSIS OF THE BIOCHEMICAL AND CELLULAR ACTIVITIES OF SUBSTRATE BINDING BY THE MOLECULAR CHAPERONE HSP110/SSE1

  2017influential citation
• Computational Analysis of Residue Interaction Networks and Coevolutionary Relationships in the Hsp70 Chaperones: A Community-Hopping Model of Allosteric Regulation and Communication

  2017cites this paper
• Protein Conformational Dynamics In Genomic Analysis

  2016cites this paper
• Chemical Modulators of Heat Shock Protein 70 (Hsp70) Validate this Molecular Chaperone as a Target for Tauopathy

  2016influential citation
• Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy.

  2016influential citation
• Emerging Computational Methods for the Rational Discovery of Allosteric Drugs

  2016cites this paper
• Probing Allosteric Inhibition Mechanisms of the Hsp70 Chaperone Proteins Using Molecular Dynamics Simulations and Analysis of the Residue Interaction Networks

  2016cites this paper
• Dynamical Structures of Hsp70 and Hsp70-Hsp40 Complexes.

  2016cites this paper
• In silico mutational studies of Hsp70 disclose sites with distinct functional attributes

  2015cites this paper
• Dancing through Life: Molecular Dynamics Simulations and Network-Centric Modeling of Allosteric Mechanisms in Hsp70 and Hsp110 Chaperone Proteins

  2015cites this paper
• Targeting the Protein Quality Control (PQC) Machinery

  2015cites this paper
• Targeting the Protein Quality Control (PQC) Machinery: The neuronal Salvation Army

  2015cites this paper
• Comparative study of the effectiveness and limitations of current methods for detecting sequence coevolution

  2015cites this paper
• GrpE, Hsp110/Grp170, HspBP1/Sil1 and BAG domain proteins: nucleotide exchange factors for Hsp70 molecular chaperones.

  2015cites this paper
• Conformational dynamics of nonsynonymous variants at protein interfaces reveals disease association

  2015cites this paper
• The Role of Conformational Dynamics and Allostery in the Disease Development of Human Ferritin.

  2015cites this paper
• Yeast Hsp70 and J-protein Chaperones: Function and Interaction Network

  2014influential citation
• ATPase Subdomain IA Is a Mediator of Interdomain Allostery in Hsp70 Molecular Chaperones

  2014influential citation
• Evol and ProDy for bridging protein sequence evolution and structural dynamics

  2014cites this paper
• Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle

  2013cites this paper
• Structural Dynamics and Allosteric Signaling in Ionotropic Glutamate Receptors

  2013cites this paper
• Identification of Key Hinge Residues Important for Nucleotide-Dependent Allostery in E. coli Hsp70/DnaK

  2013cites this paper
• Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78

  2013influential citation
• Binding of Human Nucleotide Exchange Factors to Heat Shock Protein 70 (Hsp70) Generates Functionally Distinct Complexes in Vitro*

  2013cites this paper
• Structural dynamics flexibility informs function and evolution at a proteome scale

  2013cites this paper
• Decipher the Mechanisms of Protein Conformational Changes Induced by Nucleotide Binding through Free-Energy Landscape Analysis: ATP Binding to Hsp70

  2013cites this paper
• System level mechanisms of adaptation, learning, memory formation and evolvability: the role of chaperone and other networks.

  2012cites this paper
• Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations

  2012cites this paper
• Sequence Evolution Correlates with Structural Dynamics

  2012influential citation
• Collective Dynamics Differentiates Functional Divergence in Protein Evolution

  2012cites this paper
• Crystal Structure of DnaK Protein Complexed with Nucleotide Exchange Factor GrpE in DnaK Chaperone System

  2012cites this paper
• 9.3 In Silico Coarse-Grained Approaches to Structural Dynamics and Function of Proteins and their Assemblies

  2012cites this paper
• Structure and dynamics of molecular networks: A novel paradigm of drug discovery. A comprehensive review

  2012influential citation
• Combining sequence and structure information to model biological systems dynamics

  2011influential citation
• A career pathway in protein folding: From model peptides to postreductionist protein science

  2011cites this paper
• Structure‐based, biophysical annotation of molecular coevolution of acetylcholinesterase

  2011cites this paper
• CONFORMATIONAL DYNAMICS OF PROTEINS: INSIGHTS FROM STRUCTURAL AND COMPUTATIONAL STUDIES

  2011cites this paper
• Allosteric signal transmission in the nucleotide-binding domain of 70-kDa heat shock protein (Hsp70) molecular chaperones

  2011cites this paper
• Components of a Protein Machine: Allosteric Domain Assembly and a Disordered C-terminus Enable the Chaperone Functions of Hsp70

  2011cites this paper
• Identification of key residues for protein conformational transition using elastic network model.

  2011cites this paper
• Send Orders of Reprints at Reprints@benthamscience.net Allo-network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

  year unknowncites this paper