Autoinhibition and Polo-dependent multisite phosphorylation restrict activity of the histone H3 kinase Haspin to mitosis

Mol Cell. 2013 Dec 12;52(5):734-45. doi: 10.1016/j.molcel.2013.10.002. Epub 2013 Oct 31.

Abstract

The mitosis-specific phosphorylation of histone H3 at Thr3 (H3T3ph) plays an important role in chromosome segregation by recruiting Aurora B. H3T3 phosphorylation is catalyzed by Haspin, an atypical protein kinase whose kinase domain is intrinsically active without phosphorylation at the activation loop. Here, we report the molecular basis for Haspin inhibition during interphase and its reactivation in M phase. We identify a conserved basic segment that autoinhibits Haspin during interphase. This autoinhibition is neutralized when Cdk1 phosphorylates the N terminus of Haspin in order to recruit Polo-like kinase (Plk1/Plx1), which, in turn, further phosphorylates multiple sites at the Haspin N terminus. Although Plx1, and not Aurora B, is critical for H3T3 phosphorylation in Xenopus egg extracts, Plk1 and Aurora B both promote this modification in human cells. Thus, M phase-specific H3T3 phosphorylation is governed by the combinatorial action of mitotic kinases that neutralizes Haspin autoinhibition through a mechanism dependent on multisite phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aurora Kinase B / genetics
  • Aurora Kinase B / metabolism
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Division / genetics
  • Cell Line, Tumor
  • Conserved Sequence
  • HeLa Cells
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Interphase / genetics
  • Mitosis / genetics*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism*
  • Xenopus laevis

Substances

  • Cell Cycle Proteins
  • Histones
  • Xenopus Proteins
  • Aurora Kinase B
  • Plk1 protein, Xenopus
  • Protein-Serine-Threonine Kinases
  • aurkb protein, Xenopus
  • haspin protein, Xenopus laevis
  • CDC2 Protein Kinase