The Mad2 spindle checkpoint protein has two distinct natively folded states

Xuelian Luo, Zhanyun Tang, Guohong Xia, Katia Wassmann, Tomohiro Matsumoto, Jose Rizo-Rey, Hongtao Yu

Research output: Contribution to journalArticlepeer-review

206 Scopus citations

Abstract

The spindle checkpoint delays chromosome segregation in response to misaligned sister chromatids during mitosis, thus ensuring the fidelity of chromosome inheritance. Through binding to Cdc20, the Mad2 spindle checkpoint protein inhibits the target of this checkpoint, the ubiquitin protein ligase APC/CCdc20. We now show that without cofactor binding or covalent modification Mad2 adopts two distinct folded conformations at equilibrium (termed N1-Mad2 and N2-Mad2). The structure of N2-Mad2 has been determined by NMR spectroscopy. N2-Mad2 is much more potent in APC/C inhibition. Overexpression of a Mad2 mutant that specifically sequesters N2-Mad2 partially blocks checkpoint signaling in living cells. The two Mad2 conformers interconvert slowly in vitro, but interconversion is accelerated by a fragment of Mad1, an upstream regulator of Mad2. Our results suggest that the unusual two-state behavior of Mad2 is critical for spindle checkpoint signaling.

Original languageEnglish (US)
Pages (from-to)338-345
Number of pages8
JournalNature Structural and Molecular Biology
Volume11
Issue number4
DOIs
StatePublished - Apr 2004

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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