@article {Clouser750646, author = {Amanda F. Clouser and Hannah E.R. Baughman and Benjamin Basanta and Miklos Guttman and Abhinav Nath and Rachel E. Klevit}, title = {Interplay of disordered and ordered regions of a human small heat shock protein yields an ensemble of {\textquotedblleft}quasi-ordered{\textquotedblright} states}, elocation-id = {750646}, year = {2019}, doi = {10.1101/750646}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Small heat shock proteins (sHPSs) are nature{\textquoteright}s {\textquotedblleft}first responders{\textquotedblright} to cellular stress, interacting with affected proteins to prevent their aggregation. Little is known about sHSP structure beyond its structured α-crystallin domain (ACD), which is flanked by disordered regions. In the human sHSP HSPB1, the disordered N-terminal region (NTR) represents nearly 50\% of the sequence. Here, we present a hybrid approach involving NMR, hydrogen-deuterium exchange mass spectrometry, and modeling to provide the first residue-level characterization of the NTR. The results support a model in which multiple grooves on the ACD interact with specific NTR regions, creating an ensemble of {\textquotedblleft}quasi-ordered{\textquotedblright} NTR states that can give rise to the known heterogeneity and plasticity of HSPB1. Phosphorylation-dependent interactions inform a mechanism by which HSPB1 is activated under stress conditions. Additionally, we examine the effects of disease-associated NTR mutations on HSPB1 structure and dynamics, leveraging our emerging structural insights.}, URL = {https://www.biorxiv.org/content/early/2019/08/29/750646}, eprint = {https://www.biorxiv.org/content/early/2019/08/29/750646.full.pdf}, journal = {bioRxiv} }