Small heat-shock proteins (sHSPs) are molecular chaperones that bind to unfolded proteins to prevent protein aggregation and defend against cellular stress. Mutations in human sHSPs are associated with inherited diseases including cataract and cardiomyopathy. The study was published in the journal Structure.

Individual sHSPs bind to each other to form oligomers. Hassane Mchaourab, Ph.D., and colleagues previously discovered that insertion of a small peptide into a bacterial sHSP could cause it to expand from a 24-subunit oligomer to a 48-subunit oligomer.

Previously, we discovered that the archaeal Hsp16.5, which forms ordered and symmetric 24-subunit oligomers, can be engineered to transition to an ordered and symmetric 48-subunit oligomer by insertion of a peptide from human HspB1 (Hsp27).

Here, we uncovered the existence of an array of oligomeric states (30-38 subunits) that can be populated as a consequence of altering the sequence and length of the inserted peptide. Polydisperse Hsp16.5 oligomers displayed a higher affinity to a model protein consistent with a general mechanism for recognition and binding that involves increased access to the hydrophobic N-terminal region.


Our findings, which integrate structural and functional analyzes from evolutionarily distant sHSPs, support a model where the modular architecture of these proteins encodes motifs of oligomer polydispersity, dissociation, and expansion to achieve functional diversity and regulation.

The investigators wondered if flexibility in the structure of oligomers contributes to sHSP function. Now, in studies led by Sanjay Mishra, Ph.D., they showed that altering the sequence and length of the inserted peptide generates an array of oligomers with 30 to 38 subunits.


The non-uniform collection of oligomers bound to a model protein with higher affinity. They support a model in which modular sHSP architecture contributes to the ability of sHSPs to serve as chaperones for a range of unfolded proteins.