Structural insights into an atypical histone binding mechanism by a PHD finger

Grégoire, Sabrina, Grégoire, Janelle, Yang, Yidai, Capitani, Sabrina, Joshi, Monika, Sarvan, Sabina, Zaker, Arvin, Ning, Zhibin, Figeys, Daniel, Ulrich, Kathrin, Brunzelle, Joseph S., Mer, Arvind and Couture, Jean Francois (2024) Structural insights into an atypical histone binding mechanism by a PHD finger. Structure, 32 (9). 1498-1506.e4. ISSN 1878-4186

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Abstract

Complex associating with SET1 (COMPASS) is a histone H3K4 tri-methyltransferase controlled by several regulatory subunits including CXXC zinc finger protein 1 (Cfp1). Prior studies established the structural underpinnings controlling H3K4me3 recognition by the PHD domain of Cfp1’s yeast homolog (Spp1). However, metazoans Cfp1PHD lacks structural elements important for H3K4me3 stabilization in Spp1, suggesting that in metazoans, Cfp1PHD domain binds H3K4me3 differently. The structure of Cfp1PHD in complex with H3K4me3 shows unique features such as non-canonical coordination of the first zinc atom and a disulfide bond forcing the reorientation of Cfp1PHD N-terminus, thereby leading to an atypical H3K4me3 binding pocket. This configuration minimizes Cfp1PHD reliance on canonical residues important for histone binding functions of other PHD domains. Cancer-related mutations in Cfp1PHD impair H3K4me3 binding, implying a potential impact on epigenetic signaling. Our work highlights a potential diversification of PHD histone binding modes and the impact of cancer mutations on Cfp1 functions.

Item Type:	Article
Uncontrolled Keywords:	structural biology,molecular biology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1315
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Related URLs:	http://www.scopus.com/inward/record.url?... https://www.ncbi.nlm.nih.gov/pubmed/3902...
Depositing User:	LivePure Connector
Date Deposited:	01 Oct 2025 12:30
Last Modified:	11 Oct 2025 10:14
URI:	https://ueaeprints.uea.ac.uk/id/eprint/100584
DOI:	10.1016/j.str.2024.06.017

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