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  Determinants of conformational dimerization of Mad2 and its inhibition by p31comet

Mapelli, M., Filipp, F. V., Rancati, G., Massimiliano, L., Nezi, L., Stier, G., et al. (2006). Determinants of conformational dimerization of Mad2 and its inhibition by p31comet. EMBO JOURNAL, 25(6), 1273-1284. doi:10.1038/sj.emboj.7601033.

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 Creators:
Mapelli, Marina1, Author
Filipp, Fabian V.2, Author
Rancati, Giulia3, Author
Massimiliano, Lucia1, Author
Nezi, Luigi1, Author
Stier, Gunter2, Author
Hagan, Robert S.4, Author
Confalonieri, Stefano5, Author
Piatti, Simonetta3, Author
Sattler, Michael2, Author
Musacchio, Andrea6, Author           
Affiliations:
1Department of Experimental Oncology, European Institute of Oncology, Milan, Italy, ou_persistent22              
2European Molecular Biology Laboratory, Heidelberg, Germany, ou_persistent22              
3Dipartimento di Biotecnologie e Bioscienze, Universita' di Milano‐Bicocca, Milano, Italy, ou_persistent22              
4Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA, USA, ou_persistent22              
5The FIRC Institute of Molecular Oncology Foundation, Milan, Italy, ou_persistent22              
6Abt. I:Mechanistische Zellbiologie, Max Planck Institute of Molecular Physiology, Max Planck Society, ou_1753287              

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 Abstract: The spindle assembly checkpoint (SAC) monitors chromosome attachment to spindle microtubules. SAC proteins operate at kinetochores, scaffolds mediating chromosome-microtubule attachment. The ubiquitous SAC constituents Mad1 and Mad2 are recruited to kinetochores in prometaphase. Mad2 sequesters Cdc20 to prevent its ability to mediate anaphase onset. Its function is counteracted by p31(comet) (formerly CMT2). Upon binding Cdc20, Mad2 changes its conformation from O-Mad2 (Open) to C-Mad2 (Closed). A Mad1-boundC-Mad2 template, to which O-Mad2 binds prior to being converted into Cdc20-bound C-Mad2, assists this process. A molecular understanding of this prion-like property of Mad2 is missing. We characterized the molecular determinants of the O-Mad2:C-Mad2 conformational dimer and derived a rationalization of the binding interface in terms of symmetric and asymmetric components. Mutation of individual interface residues abrogates the SAC in Saccharomyces cerevisiae. NMR chemical shift perturbations indicate that O-Mad2 undergoes a major conformational rearrangement upon binding C-Mad2, suggesting that dimerization facilitates the structural conversion of O-Mad2 required to bind Cdc20. We also show that the negative effects of p31(comet) on the SAC are based on its competition with O-Mad2 for C-Mad2 binding.

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 Dates: 2006
 Publication Status: Issued
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 Identifiers: ISI: 000236737700010
DOI: 10.1038/sj.emboj.7601033
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Title: EMBO JOURNAL
Source Genre: Journal
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Pages: - Volume / Issue: 25 (6) Sequence Number: - Start / End Page: 1273 - 1284 Identifier: ISSN: 0261-4189