Heat shock protein Hsc70/Hsp110 complex
Heat shock protein(Hsp) are diverse sets of proteins whose expressions are increased in response to high temperature stress. In many cases, their expressions can also be promoted by several kinds of stress factors other than high temperature: heavy metal, active enzyme, or ethanol. Therefore, Hsps may be regarded as stress protein. Hsps are usually classified into several families based on their approximate molecular weights (Fig.1).
In order to function correctly, proteins need to fold into correct tertiary structure. However, several proteins which can't fold into native conformation by one's own or misfolded proteins which folded into incorrect conformation require the assist of chaperone proteins for folding(or refolding) into native conformation. Most chaperones are known to be Hsp (*1). The chaperone mechanisms of well-known three Hsp families(i.e. Hsp60, Hsp70, Hsp90) were illustrated below (Fig.2, 3, 4).
In these mechanisms, the common feature for Hsps is that Hsp expresses their chaperone function by collaborating with their co-chaperone(s) in the presence of ATP. However, the details of these mechanisms remain unclear. For instance, Bag1 is known to have a role of exchanging ADT/ATP as binding to Hsc70 as seen in the Hsp70 chaperone mechanism of Fig.2. However, the manner by which the two proteins regulate ADP/ATP exchange is unknown. Hsp110, like Bag1, also has a role of exchanging ADP/ATP as a co-chaperone for Hsc70. The complex crystal structure of Hsc70 and Hsp110 revealed the ADP/ATP exchanging mechanism.
Herein, the complex structure of Hsc70 and Hsp110 was shown (*2). Both Hsps consist with two domains: a nucleotide binding domain(NBD) and a substrate binding domain(SBD). The SBD of Hsp110 is further subdivided into a alpha-structured subdomain(SBDa) and a beta-structured subdomain(SBDb) (Fig.5). In this complex, each NBD of the two Hsps contain a ADP molecule respectively.
Hsc70 and Hsp110 form a stable complex with extensive interactions between the NBDs of the two Hsps. A pore that is large enough to accommodate an ATP was found across the interface of the two NBDs. The pore connects the nucleotide-binding sites directly (Fig.5C). While the Hsp110 NBD side of the pore is closed, the Hsc70 NBD side of that is opened. This observation indicates that the ADP which is binding to the Hsc70 NBD is in prereleased state. Furthermore, it was supposed that Hsp110 SBDa pulls Hsc70 NBD by interacting with it and make the Hsc70 NBD side of the pore open. The importance of the conformational shift was verified by the experimental data: when several residues contributing to the interactions between Hsp SBDa and Hsc70 NBD were replaced, the chaperone activity was decreased. These observations revealed that the Hsp110 SBDa has a function of keeping the Hsc70 NBD side of the pore in open-state for exchanging an ADP to an ATP efficiently.
(*2) In the present complex structure, Hsc70 and Hsp110 were extracted from different species respectively: while Hsc70 was obtained from bovine, Hsp110 was taken from yeast. According to the original article, it was confirmed that the yeas Hsp110 shows high sequence identity to the bovine Hsp110 and can functionally substitute for the bovine Hsp110.
Protein Data Bank (PDB)
Schuermann, J.P. Jiang, J. Cuellar, J. Llorca, O. Wang, L. Gimenez, L.E. Jin, S. Taylor, A.B. Demeler, B. Morano, K.A. Hart, P.J. Valpuesta, J.M. Lafer, E.M. Sousa, R.; "Structure of the Hsp110:Hsc70 nucleotide exchange machine"; Mol.Cell; (2008) 31:232-243 PubMed:18550409.
author: Jun-ichi Ito