7qby

Publication Abstract from PubMed

DNAJB6 is a prime example of an anti-aggregation chaperone that functions as an oligomer. DNAJB6 oligomers are dynamic and subunit exchange is critical for inhibiting client protein aggregation. The T193A mutation in the C-terminal domain (CTD) of DNAJB6 reduces both chaperone self-oligomerization and anti-aggregation of client proteins, and has recently been linked to Parkinson's disease. Here, we show by NMR, including relaxation-based methods, that the T193A mutation has minimal effects on the structure of the beta-stranded CTD but increases the population and rate of formation of a partially folded state. The results can be rationalized in terms of beta-strand peptide plane flips that occur on a timescale of approximately 100 mus and lead to global changes in the overall pleat/flatness of the CTD, thereby altering its ability to oligomerize. These findings help forge a link between chaperone dynamics, oligomerization and anti-aggregation activity which may possibly lead to new therapeutic avenues tuned to target specific substrates.

Microsecond Backbone Motions Modulate the Oligomerization of the DNAJB6 Chaperone.,Cawood EE, Clore GM, Karamanos TK Angew Chem Int Ed Engl. 2022 Mar 5:e202116403. doi: 10.1002/anie.202116403. PMID:35247211^[1]

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