Research Papers

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

by Papita Mandal, Karthik Eswara, Zhadyra Yerkesh, Vladlena Kharchenko, Levani Zandrarashvili, Kacper Szczepski, Dalila Bensaddek, Łukasz Jaremko, Ben E. Black, Wolfgang Fischle
Science Advances Year: 2022 DOI: doi: 10.1126/sciadv.abl9461


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.


hUHRF1 Histones PI5P