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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 activiti...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401617/ https://www.ncbi.nlm.nih.gov/pubmed/36001657 http://dx.doi.org/10.1126/sciadv.abl9461 |
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author | Mandal, Papita Eswara, Karthik Yerkesh, Zhadyra Kharchenko, Vladlena Zandarashvili, Levani Szczepski, Kacper Bensaddek, Dalila Jaremko, Łukasz Black, Ben E. Fischle, Wolfgang |
author_facet | Mandal, Papita Eswara, Karthik Yerkesh, Zhadyra Kharchenko, Vladlena Zandarashvili, Levani Szczepski, Kacper Bensaddek, Dalila Jaremko, Łukasz Black, Ben E. Fischle, Wolfgang |
author_sort | Mandal, Papita |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9401617 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-94016172022-08-26 Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P Mandal, Papita Eswara, Karthik Yerkesh, Zhadyra Kharchenko, Vladlena Zandarashvili, Levani Szczepski, Kacper Bensaddek, Dalila Jaremko, Łukasz Black, Ben E. Fischle, Wolfgang Sci Adv Biomedicine and Life Sciences 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. American Association for the Advancement of Science 2022-08-24 /pmc/articles/PMC9401617/ /pubmed/36001657 http://dx.doi.org/10.1126/sciadv.abl9461 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Mandal, Papita Eswara, Karthik Yerkesh, Zhadyra Kharchenko, Vladlena Zandarashvili, Levani Szczepski, Kacper Bensaddek, Dalila Jaremko, Łukasz Black, Ben E. Fischle, Wolfgang Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P |
title | Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P |
title_full | Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P |
title_fullStr | Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P |
title_full_unstemmed | Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P |
title_short | Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P |
title_sort | molecular basis of huhrf1 allosteric activation for synergistic histone modification binding by pi5p |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401617/ https://www.ncbi.nlm.nih.gov/pubmed/36001657 http://dx.doi.org/10.1126/sciadv.abl9461 |
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