Conserved S/T Residues of the Human Chaperone DNAJB6 Are Required for Effective Inhibition of Aβ42 Amyloid Fibril Formation

• DOI: 10.1021/acs.biochem.8b00353
• Publication Date: 2018-07-19T19:29:19Z
• Authors: Cecilia Månsson; Remco T. P. van C...; Ulrich Weininger; Xiaoting Yang; Risto Cukalevski; Paolo Arosio; Christopher M. Do...; Tuomas Knowles; Mikael Akke; Sara Linse; Cecilia Emanuelsson
• Keywords: Chaperone (clinical); Amyloid (mycology)

The human molecular chaperone DNAJB6, an oligomeric protein with a conserved S/T-rich region, is efficient suppressor of amyloid fibril formation by highly aggregation-prone peptides such as the Aβ and polyQ associated Alzheimer's Huntington's disease, respectively. We previously showed that DNAJB6 can inhibit processes through which fibrils are formed via strong interactions aggregated forms Aβ42 become sequestered. Here we report concentration-dependent capability to suppress in thioflavin T fluorescence assays decreases progressively increasing number S/T substitutions, almost complete loss suppression when 18 residues substituted. kinetics primary nucleation particular affected. No detectable changes structure caused substitutions. Also, level binding determined surface plasmon resonance microscale thermophoresis. aggregation process monitored using nuclear magnetic spectroscopy contrast mutational variant substituted, keep monomeric soluble for extended time. inhibition likely depend on hydroxyl groups side chains residues, hydrogen bonding one plausible mechanism, although other possibilities cannot be excluded. ability upon A substitution was observed also peptides, suggesting DNAJB6-like chaperones have general different peptides.