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bioRxiv · 10.1101/2024.12.03.626587

Coevolution in Small Heat Shock Protein 1 (HSPB1) is Promoted by Interactions between the Alpha-Crystallin Domain and the Disordered Regions

Racigh, V.·Fornasari, M. S.·Rodriguez Sawicki, L.·Bravo, F. N. E.
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Abstract

Human HSPB1, a member of the small heat shock protein (sHSP) family, functions as an ATP-independent molecular chaperone crucial for protein quality control and is implicated in several pathologies, including Charcot-Marie-Tooth neuropathy. This study investigates the coevolution of the disordered N-terminal and C-terminal regions (NTR and CTR) with the structured Alpha-Crystallin domain (ACD) of human HSPB1, focusing on interactions that regulate its chaperone activity. Using a manually curated dataset of HSPB1 orthologs, the composition of critical motifs within the NTR (6VPFSLL11) and CTR (179ITIPV183) that interact with the ACD was analyzed and evolutionary rates per site for the human HSPB1 sequence were estimated. Additionally, structural modeling with AlphaFold 2 was employed to assess the prevalence of these contacts in human HSPB1 models. The results reveal that while the disordered regions globally evolve faster than the structured ACD, specific residues within the 6VPFSLL11 and 179ITIPV183 motifs exhibit reduced evolutionary rates, reflecting evolutionary constraints imposed by the conservation of the proteins function. Structural modeling further indicates that coevolutionary-like information about the interaction between the 6VPFSLL11 motif and the ACD is encoded in the multiple sequence alignment used by Alphafold 2. Altogether, these findings suggest that the disordered regions and the ACD of human HSPB1 likely coevolved, preserving interactions crucial for its chaperone activity self-regulation. This evolutionary mechanism may also be extended to other sHSP featuring interacting motifs in the NTR, CTR, or both, and provides a framework to elucidate why pathogenic variants occurring in regions involved in these contacts contribute to disease.

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Racigh, V., Fornasari, M. S., Rodriguez Sawicki, L., Bravo, F. N. E.. 2024-12-04. Coevolution in Small Heat Shock Protein 1 (HSPB1) is Promoted by Interactions between the Alpha-Crystallin Domain and the Disordered Regions. https://doi.org/10.1101/2024.12.03.626587

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