Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P

Chromatin marks are recognized by distinct binding modules, many of which are embedded in multidomain proteins. How the different functionalities of such complex chromatin modulators are regulated is often unclear. Here, we delineated the interplay of the H3 amino terminus– and K9me-binding activities of the multidomain hUHRF1 protein. We show that the phosphoinositide PI5P interacts simultaneously with two distant flexible linker regions connecting distinct domains of hUHRF1. The binding is dependent on both, the polar head group, and the acyl part of the phospholipid and induces a conformational rearrangement juxtaposing the H3 amino terminus and K9me3 recognition modules of the protein. In consequence, the two features of the H3 tail are bound in a multivalent, synergistic manner. Our work highlights a previously unidentified molecular function for PI5P outside of the context of lipid mono- or bilayers and establishes a molecular paradigm for the allosteric regulation of complex, multidomain chromatin modulators by small cellular molecules.

Mandal, P., Eswara, K., Yerkesh, Z., Kharchenko, V., Zandarashvili, L., Szczepski, K., Bensaddek, D., Jaremko, Ł., Black, B. E., & Fischle, W. (2022). Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P. Science Advances, 8(34).

We thank A. Aljahani for help with MST assays, S. Kreuz for scientific input during this study, and members of the Fischle laboratory for discussions. This work was supported by the King Abdullah University of Science and Technology (intramural funds and award OSR-2015-CRG-2616 of the KAUST Office of Sponsored Research to W.F.) and NIH grants R35GM130302 (to B.E.B.) and F32GM128265 (to L.Z.).

American Association for the Advancement of Science (AAAS)

Science Advances


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