A mechanism of action for small heat shock proteins

Molecular dynamics simulations of a fitted multimeric structure of Mycobacterium tuberculosis α-crystallin (Mtb Acr) identify solvent exclusion from the β4–β8 hydrophobic groove as a critical factor driving subunit assembly. Dehydration is also implicated as a determinant factor governing the chaperone activity of the dimer upon its dissociation from the oligomer. Two exposed hydrogen bonds, responsible for stabilizing the β8–β9 fold are identified as key mechanistic elements in this process. Based on the overproduction of the chemokine CXCL16, observed after macrophage exposure to Mtb Acr, the proteases ADAM10 and ADAM17 are mooted as possible targets of this chaperone activity.

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► Molecular dynamics simulations of fitted multimeric structure of Mtb Acr.
► Solvent exclusion identified as a critical factor driving subunit assembly.
► Exposed hydrogen bonds identified as a structural vulnerability.
► Sequence alignments and homologies used to probe hydrophobic groove.