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 (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 β‐stranded CTD but increases the population and rate of formation of a partially folded state. The results can be rationalized in terms of β‐strand peptide plane flips that occur on a timescale of ≈100 μs 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. Chaperone self‐oligomerization that competes with substrate assembly is an important aspect of anti‐aggregation chaperones that remains poorly understood. Using the J domain chaperone DNAJB6, how the Parkinson's related T193A mutation affects chaperone oligomerization has been explored. The C‐terminal domain of DNAJB6b exhibits significant microsecond dynamics that are enhanced in the T193A mutant, leading to a monomeric partially‐folded state.