Microsecond Backbone Motions Modulate the Oligomerization of the DNAJB6 Chaperone

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 (CID) 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 CID 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 approximate to 100 mu s 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.

Automated summary

The T193A mutation in DNAJB6 reduces self-oligomerization and anti-aggregation activity while increasing the rate of formation of a partially folded state. This highlights the importance of chaperone dynamics in regulating protein aggregation and suggests potential therapeutic avenues targeting specific substrates.