p31comet blocks Mad2 activation through structural mimicry

Cell. 2007 Nov 16;131(4):744-55. doi: 10.1016/j.cell.2007.08.048.

Abstract

The status of spindle checkpoint signaling depends on the balance of two opposing dynamic processes that regulate the highly unusual two-state behavior of Mad2. In mitosis, a Mad1-Mad2 core complex recruits cytosolic Mad2 to kinetochores through Mad2 dimerization and converts Mad2 to a conformer amenable to Cdc20 binding, thereby facilitating checkpoint activation. p31(comet) inactivates the checkpoint through binding to Mad1- or Cdc20-bound Mad2, thereby preventing Mad2 activation and promoting the dissociation of the Mad2-Cdc20 complex. Here, we report the crystal structure of the Mad2-p31(comet) complex. The C-terminal region of Mad2 that undergoes rearrangement in different Mad2 conformers is a major structural determinant for p31(comet) binding, explaining the specificity of p31(comet) toward Mad1- or Cdc20-bound Mad2. p31(comet) adopts a fold strikingly similar to that of Mad2 and binds at the dimerization interface of Mad2. Thus, p31(comet) exploits the two-state behavior of Mad2 to block its activation by acting as an "anti-Mad2."

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Allosteric Regulation
  • Amino Acid Sequence
  • Animals
  • Calcium-Binding Proteins / chemistry*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cell Cycle / physiology
  • Cell Cycle Proteins / chemistry*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • Mad2 Proteins
  • Models, Molecular
  • Molecular Mimicry*
  • Molecular Sequence Data
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Nocodazole / metabolism
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary*
  • Repressor Proteins / chemistry*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Sequence Alignment
  • Tubulin Modulators / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • MAD2L1 protein, human
  • MAD2L1BP protein, human
  • Mad2 Proteins
  • Multiprotein Complexes
  • Nuclear Proteins
  • Repressor Proteins
  • Tubulin Modulators
  • Nocodazole

Associated data

  • PDB/2QYF