The Mad2 conformational dimer: structure and implications for the spindle assembly checkpoint.
The 25 kDa Mad2 protein is a key player in the spindle assembly checkpoint, a safeguard against chromosome segregation errors in mitosis. Mad2 combines three unusual properties. First, Mad2 adopts two conformations with distinct topologies, open (O) and closed (C) Mad2. Second, C-Mad2 forms topological links with its two best-characterized protein ligands, Mad1 and Cdc20. Third, O-Mad2 and C-Mad2 engage in a "conformational" dimer that is essential for spindle checkpoint function in different organisms. The crystal structure of the O-Mad2-C-Mad2 conformational dimer, reported here, reveals an asymmetric interface that explains the selective dimerization of the O-Mad2 and C-Mad2 conformers. The structure also identifies several buried hydrophobic residues whose rearrangement correlates with the Mad2 topological change. The structure of the O-Mad2-C-Mad2 conformational dimer is consistent with a catalytic model in which a C-Mad2 template facilitates the binding of O-Mad2 to Cdc20, the target of Mad2 in the spindle checkpoint.
Mapelli
Marina
M
Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, I-20139, Milan, Italy. marina.mapelli@ifom-ieo-campus.it
Massimiliano
Lucia
L
Santaguida
Stefano
S
Musacchio
Andrea
A
D000595:Amino Acid Sequence; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D064246:Mad2 Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D012097:Repressor Proteins