7JSQ

Refined structure of the C-terminal domain of DNAJB6b

Summary for 7JSQ

• Entry DOI: 10.2210/pdb7jsq/pdb
• Related: 6U3R 6U3S
• NMR Information: BMRB: 30656
• Descriptor: DnaJ homolog subfamily B member 6 (1 entity in total)
• Functional Keywords: chaperone, anti-aggregation, hsp40
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 6474.40

Authors

Karamanos, T.K.,Clore, G.M. (deposition date: 2020-08-15, release date: 2020-12-02, Last modification date: 2024-05-01)

Primary citation

Karamanos, T.K.,Tugarinov, V.,Clore, G.M.
An S/T motif controls reversible oligomerization of the Hsp40 chaperone DNAJB6b through subtle reorganization of a beta sheet backbone.
Proc.Natl.Acad.Sci.USA, 117:30441-30450, 2020

PubMed Abstract: Chaperone oligomerization is often a key aspect of their function. Irrespective of whether chaperone oligomers act as reservoirs for active monomers or exhibit a chaperoning function themselves, understanding the mechanism of oligomerization will further our understanding of how chaperones maintain the proteome. Here, we focus on the class-II Hsp40, human DNAJB6b, a highly efficient inhibitor of protein self-assembly in vivo and in vitro that forms functional oligomers. Using single-quantum methyl-based relaxation dispersion NMR methods we identify critical residues for DNAJB6b oligomerization in its C-terminal domain (CTD). Detailed solution NMR studies on the structure of the CTD showed that a serine/threonine-rich stretch causes a backbone twist in the N-terminal β strand, stabilizing the monomeric form. Quantitative analysis of an array of NMR relaxation-based experiments (including Carr-Purcell-Meiboom-Gill relaxation dispersion, off-resonance profiles, lifetime line broadening, and exchange-induced shifts) on the CTD of both wild type and a point mutant (T142A) within the S/T region of the first β strand delineates the kinetics of the interconversion between the major twisted-monomeric conformation and a more regular β strand configuration in an excited-state dimer, as well as exchange of both monomer and dimer species with high-molecular-weight oligomers. These data provide insights into the molecular origins of DNAJB6b oligomerization. Further, the results reported here have implications for the design of β sheet proteins with tunable self-assembling properties and pave the way to an atomic-level understanding of amyloid inhibition.

PubMed: 33199640
DOI: 10.1073/pnas.2020306117

Experimental method

SOLUTION NMR