9R6H

Crystal Structure of the M18BP1 SANTA domain as a EGFP-SANTA-nanobody fusion

Summary for 9R6H

• Entry DOI: 10.2210/pdb9r6h/pdb
• Descriptor: Genome polyprotein,Mis18-binding protein 1,Chains: A, TETRAETHYLENE GLYCOL (3 entities in total)
• Functional Keywords: centromere binding, mitotic kinetochores, cenp-a loading, mis18 complex, cell cycle
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 112899.28

Authors

Pan, D.,Vetter, I.R.,Musacchio, A. (deposition date: 2025-05-12, release date: 2026-01-14, Last modification date: 2026-03-11)

Primary citation

Walstein, K.,Hill, L.,Vogt, D.,Oberste-Lehn, L.,Janning, P.,Vetter, I.R.,Pan, D.,Musacchio, A.
M18BP1 valency and a distributed interaction footprint determine epigenetic centromere specification in humans.
Embo J., 45:1537-1572, 2026

PubMed Abstract: The histone H3 variant CENP-A is considered an epigenetic landmark of centromeres. Its deposition reflects cell-cycle-regulated assembly of M18BP1, HJURP, and PLK1 on a divalent MIS18α/β scaffold. The localization determinants of this machinery remain poorly characterized. Here, we report that in human cells, artificial M18BP1 dimerization bypasses MIS18α/β, allowing the identification of at least four determinants of M18BP1 centromere localization. These include the SANTA domain, of which we report the first structure, as well as linear motifs in disordered neighboring regions, of which we characterize the interaction footprint on the CENP-A-associated 16-subunit constitutive centromere-associated network (CCAN). Our observations imply that M18BP1, after dimerization, is necessary and sufficient for centromere localization. Its cell-cycle-dependent dimerization on MIS18α/β promotes initial recognition of a multivalent centromeric assembly of old CENP-A and associated proteins, followed by cooption of PLK1 and HJURP and new CENP-A deposition. Our results shed new light on the determinants of centromere epigenetic inheritance in humans.

PubMed: 41629527
DOI: 10.1038/s44318-026-00698-z

Experimental method

X-RAY DIFFRACTION (2.42 Å)