Form Meets Function: Oligomerisation Propensity and the Anti-Amyloid Activity of DNAJB6b

Sammanfattning

The chaperone protein DNAJB6b exhibits intrinsic activity in inhibiting amyloid fibril formation, although the underlying mechanism remains unclear. A key region, comprising residues 132-183 and rich in serine and threonine residues, commonly referred to as the “S/T region”, has been shown to play a critical role in this function. While deletion of the S/T region does not disrupt the folding of DNAJB6b’s N- and C-terminal domains, it markedly reduces the anti-amyloid activity of the chaperone and disrupts its ability to form polydisperse oligomers, resulting instead in a monomeric protein in solution. In this study, we investigated the role of the S/T region by characterizing mutants with partial deletions within this segment. By comparing the first and second halves of the region, we show that oligomerisation is driven by the specific residues or segments rather than linker length. We also observed phase separation in two of the deletion mutants. Our findings also suggest that the features governing oligomerisation and chaperone activity are indirectly linked, and that all three investigated mutants exhibited poorer functionality compared to the full-length protein.