Substrate-Specific Activation of the Mitotic Kinase Bub1 through Intramolecular Autophosphorylation and Kinetochore Targeting

Zhonghui Lin, Luying Jia, Diana R. Tomchick, Xuelian Luo, Hongtao Yu

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

During mitosis of human cells, the kinase Bub1 orchestrates chromosome segregation through phosphorylating histone H2A and the anaphase-promoting complex/cyclosome activator Cdc20. Bub1-mediated H2A-T120 phosphorylation (H2A-pT120) at kinetochores promotes centromeric sister-chromatid cohesion, whereas Cdc20 phosphorylation by Bub1 contributes to spindle checkpoint signaling. Here, we show that phosphorylation at the P+1 substrate-binding loop of human Bub1 enhances its activity toward H2A but has no effect on its activity toward Cdc20. We determine the crystal structure of phosphorylated Bub1. A comparison between structures of phosphorylated and unphosphorylated Bub1 reveals phosphorylation-triggered reorganization of the P+1 loop. This activating phosphorylation of Bub1 is constitutive during the cell cycle. Enrichment of H2A-pT120 at mitotic kinetochores requires kinetochore targeting of Bub1. The P+1 loop phosphorylation of Bub1 appears to occur through intramolecular autophosphorylation. Our study provides structural and functional insights into substrate-specific regulation of a key mitotic kinase and expands the repertoire of kinase activation mechanisms.

Original languageEnglish (US)
Pages (from-to)1616-1627
Number of pages12
JournalStructure
Volume22
Issue number11
DOIs
StatePublished - Nov 4 2014

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Substrate-Specific Activation of the Mitotic Kinase Bub1 through Intramolecular Autophosphorylation and Kinetochore Targeting'. Together they form a unique fingerprint.

  • Cite this