AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity

Abstract

The ataxia-linked protein sacsin has three regions of partial homology to Hsp90's N-terminal ATP binding domain. Although a crystal structure for the Hsp90-like domain of sacsin has been reported the precise molecular interactions required for ATP-binding and hydrolysis are unclear. To better understand how sacsin may function as an ATPase we utilized an AlphaFold predicted structure of its Hsp90-like domain. Superimposition onto Hsp90, and other modelling approaches, have resulted in novel insights into sacsin's structure. These encompass identification of residues within the sacsin Hsp90-like domains that are required for ATP binding and hydrolysis, including the catalytic arginine residues equivalent to that of the Hsp90 middle domain. Importantly, our analysis allows comparison of the Hsp90 middle domain with corresponding sacsin regions and has identified that sacsin has a shorter lid segment than the N-terminal domain of Hsp90. We also speculate, from a structural viewpoint, why ATP competitive inhibitors of Hsp90 do not appear to affect sacsin. Together our analysis supports the hypothesis that sacsin's function is ATP-driven and would be consistent with it having a role as a molecular chaperone. We propose that the SR1 regions of sacsin be renamed as HSP-NRD (Hsp90 N-Terminal Repeat Domain; residues 84-324) and the fragment immediately after as HSP-MRD (Hsp90 Middle Repeat Domain; residues 325-518).