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ATP-driven molecular chaperone machines.

Clare DK, Saibil HR - Biopolymers (2013)

Bottom Line: This review is focused on the mechanisms by which ATP binding and hydrolysis drive chaperone machines assisting protein folding and unfolding.A survey of the key, general chaperone systems Hsp70 and Hsp90, and the unfoldase Hsp100 is followed by a focus on the Hsp60 chaperonin machine which is understood in most detail.These structures suggest a mechanism by which GroEL can forcefully unfold and then encapsulate substrates for subsequent folding in isolation from all other binding surfaces.

View Article: PubMed Central - PubMed

Affiliation: Department of Crystallography, Institute of Structural and Molecular Biology, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK.

No MeSH data available.


The Hsp70/Hsp40 chaperones. Structures of Hsp70 in the open, domain docked (a) and closed (b) conformations (PDB ID: 4B9Q and 2KHO). The nucleotide binding domains are shown in red (nucleotide is shown in gray), the substrate binding domains in blue and the C-terminal lid in cyan. (c) Structure of the C-terminal dimer of the peptide binding fragment of Hsp40 (blue) with three copies of the MEEVD peptide of Hsp70 bound to it (magenta) (PDB ID: 3AGY). Structure of the J-domain of Hsp40 (red) (PDB ID: 2O37). The black-dotted line shown in c and d indicates the connectivity of Hsp40 domains. All figures have been made with UCSF Chimera.18
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fig01: The Hsp70/Hsp40 chaperones. Structures of Hsp70 in the open, domain docked (a) and closed (b) conformations (PDB ID: 4B9Q and 2KHO). The nucleotide binding domains are shown in red (nucleotide is shown in gray), the substrate binding domains in blue and the C-terminal lid in cyan. (c) Structure of the C-terminal dimer of the peptide binding fragment of Hsp40 (blue) with three copies of the MEEVD peptide of Hsp70 bound to it (magenta) (PDB ID: 3AGY). Structure of the J-domain of Hsp40 (red) (PDB ID: 2O37). The black-dotted line shown in c and d indicates the connectivity of Hsp40 domains. All figures have been made with UCSF Chimera.18

Mentions: Hsp70's are formed of a 44 kDa N-terminal ATPase domain and a 28 kDa substrate binding domain with a C-terminal lid subdomain16,17 (Figure 1). The ATPase domain of Hsp70 has a similar fold to that of the functionally unrelated proteins actin and hexokinase.19 The substrate-binding domain is a flat, brick shape with a channel that binds extended polypeptide chains, covered by the flexible lid subdomain. In the ATP bound conformation of Hsp70, the lid is more likely to be open, giving a low affinity for substrate.20,21 ATP binding and subsequent closure of the nucleotide cleft creates a binding site on the ATPase domain for the interdomain linker. This linker docked conformation then recruits the substrate-binding domain to bind to the ATPase domain in a very open conformation favoring substrate binding.20 Substrate binding stimulates the Hsp70 ATPase, releasing the substrate binding domain and allowing the lid subdomain to close over the substrate-binding site, locking the substrate in place.22 A nucleotide exchange factor is required to release ADP and allow ATP into the nucleotide-binding site to re-open the lid and release substrate.23,24 This resets Hsp70 ready for the next substrate and gives the released substrate the opportunity to fold correctly.


ATP-driven molecular chaperone machines.

Clare DK, Saibil HR - Biopolymers (2013)

The Hsp70/Hsp40 chaperones. Structures of Hsp70 in the open, domain docked (a) and closed (b) conformations (PDB ID: 4B9Q and 2KHO). The nucleotide binding domains are shown in red (nucleotide is shown in gray), the substrate binding domains in blue and the C-terminal lid in cyan. (c) Structure of the C-terminal dimer of the peptide binding fragment of Hsp40 (blue) with three copies of the MEEVD peptide of Hsp70 bound to it (magenta) (PDB ID: 3AGY). Structure of the J-domain of Hsp40 (red) (PDB ID: 2O37). The black-dotted line shown in c and d indicates the connectivity of Hsp40 domains. All figures have been made with UCSF Chimera.18
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3814418&req=5

fig01: The Hsp70/Hsp40 chaperones. Structures of Hsp70 in the open, domain docked (a) and closed (b) conformations (PDB ID: 4B9Q and 2KHO). The nucleotide binding domains are shown in red (nucleotide is shown in gray), the substrate binding domains in blue and the C-terminal lid in cyan. (c) Structure of the C-terminal dimer of the peptide binding fragment of Hsp40 (blue) with three copies of the MEEVD peptide of Hsp70 bound to it (magenta) (PDB ID: 3AGY). Structure of the J-domain of Hsp40 (red) (PDB ID: 2O37). The black-dotted line shown in c and d indicates the connectivity of Hsp40 domains. All figures have been made with UCSF Chimera.18
Mentions: Hsp70's are formed of a 44 kDa N-terminal ATPase domain and a 28 kDa substrate binding domain with a C-terminal lid subdomain16,17 (Figure 1). The ATPase domain of Hsp70 has a similar fold to that of the functionally unrelated proteins actin and hexokinase.19 The substrate-binding domain is a flat, brick shape with a channel that binds extended polypeptide chains, covered by the flexible lid subdomain. In the ATP bound conformation of Hsp70, the lid is more likely to be open, giving a low affinity for substrate.20,21 ATP binding and subsequent closure of the nucleotide cleft creates a binding site on the ATPase domain for the interdomain linker. This linker docked conformation then recruits the substrate-binding domain to bind to the ATPase domain in a very open conformation favoring substrate binding.20 Substrate binding stimulates the Hsp70 ATPase, releasing the substrate binding domain and allowing the lid subdomain to close over the substrate-binding site, locking the substrate in place.22 A nucleotide exchange factor is required to release ADP and allow ATP into the nucleotide-binding site to re-open the lid and release substrate.23,24 This resets Hsp70 ready for the next substrate and gives the released substrate the opportunity to fold correctly.

Bottom Line: This review is focused on the mechanisms by which ATP binding and hydrolysis drive chaperone machines assisting protein folding and unfolding.A survey of the key, general chaperone systems Hsp70 and Hsp90, and the unfoldase Hsp100 is followed by a focus on the Hsp60 chaperonin machine which is understood in most detail.These structures suggest a mechanism by which GroEL can forcefully unfold and then encapsulate substrates for subsequent folding in isolation from all other binding surfaces.

View Article: PubMed Central - PubMed

Affiliation: Department of Crystallography, Institute of Structural and Molecular Biology, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK.

No MeSH data available.