4po2

Publication Abstract from PubMed

The HSP70 family of molecular chaperones function to maintain protein quality control and homeostasis. The major stress-induced form, HSP70 (also called HSP72 or HSPA1A) is considered an important anti-cancer drug target because it is constitutively overexpressed in a number of human cancers and promotes cancer cell survival. All HSP70 family members contain two functional domains: an N-terminal nucleotide binding domain (NBD) and a C-terminal protein substrate-binding domain (SBD); the latter is subdivided into SBDalpha and SBDbeta subdomains. The NBD and SBD structures of the bacterial ortholog, DnaK, have been characterized, but only the isolated NBD and SBDalpha segments of eukaryotic HSP70 proteins have been determined. Here we report the crystal structure of the substrate-bound human HSP70-SBD to 2 angstrom resolution. The overall fold of this SBD is similar to the corresponding domain in the substrate-bound DnaK structures, confirming a similar overall architecture of the orthologous bacterial and human HSP70 proteins. However, conformational differences are observed in the peptide-HSP70-SBD complex, particularly in the loop Lalpha, beta that bridges SBDalpha to SBDbeta, and the loop LL,1 that connects the SBD and NBD. The interaction between the SBDalpha and SBDbeta subdomains and the mode of substrate recognition is also different between DnaK and HSP70. This suggests that differences may exist in how different HSP70 proteins recognize their respective substrates. The high-resolution structure of the substrate-bound-HSP70-SBD complex provides a molecular platform for the rational design of small molecule compounds that preferentially target this C-terminal domain, in order to modulate human HSP70 function.

Crystal structure of the stress-inducible human heat shock protein 70 substrate-binding domain in complex with Peptide substrate.,Zhang P, Leu JI, Murphy ME, George DL, Marmorstein R PLoS One. 2014 Jul 24;9(7):e103518. doi: 10.1371/journal.pone.0103518., eCollection 2014. PMID:25058147^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.