6VEE

Solution structure of the TTD and linker region of mouse UHRF1 (NP95)

Summary for 6VEE

• Entry DOI: 10.2210/pdb6vee/pdb
• NMR Information: BMRB: 30704
• Descriptor: E3 ubiquitin-protein ligase UHRF1 (1 entity in total)
• Functional Keywords: histone, tandem tudor domain, np95, uhrf1, h3k9me3, peptide binding protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 21690.58

Authors

Lemak, A.,Houliston, S.,Duan, S.,Arrowsmith, C.H. (deposition date: 2019-12-31, release date: 2020-06-17, Last modification date: 2024-05-15)

Primary citation

Tauber, M.,Kreuz, S.,Lemak, A.,Mandal, P.,Yerkesh, Z.,Veluchamy, A.,Al-Gashgari, B.,Aljahani, A.,Cortes-Medina, L.V.,Azhibek, D.,Fan, L.,Ong, M.S.,Duan, S.,Houliston, S.,Arrowsmith, C.H.,Fischle, W.
Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1.
Nucleic Acids Res., 48:7728-7747, 2020

PubMed Abstract: UHRF1 is an important epigenetic regulator associated with apoptosis and tumour development. It is a multidomain protein that integrates readout of different histone modification states and DNA methylation with enzymatic histone ubiquitylation activity. Emerging evidence indicates that the chromatin-binding and enzymatic modules of UHRF1 do not act in isolation but interplay in a coordinated and regulated manner. Here, we compared two splicing variants (V1, V2) of murine UHRF1 (mUHRF1) with human UHRF1 (hUHRF1). We show that insertion of nine amino acids in a linker region connecting the different TTD and PHD histone modification-binding domains causes distinct H3K9me3-binding behaviour of mUHRF1 V1. Structural analysis suggests that in mUHRF1 V1, in contrast to V2 and hUHRF1, the linker is anchored in a surface groove of the TTD domain, resulting in creation of a coupled TTD-PHD module. This establishes multivalent, synergistic H3-tail binding causing distinct cellular localization and enhanced H3K9me3-nucleosome ubiquitylation activity. In contrast to hUHRF1, H3K9me3-binding of the murine proteins is not allosterically regulated by phosphatidylinositol 5-phosphate that interacts with a separate less-conserved polybasic linker region of the protein. Our results highlight the importance of flexible linkers in regulating multidomain chromatin binding proteins and point to divergent evolution of their regulation.

PubMed: 32609811
DOI: 10.1093/nar/gkaa520

Experimental method

SOLUTION NMR