The influence of catalysis on mad2 activation dynamics.

Mad2 is a key component of the spindle assembly checkpoint, a safety device ensuring faithful sister chromatid separation in mitosis. The target of Mad2 is Cdc20, an activator of the anaphase-promoting complex/cyclosome (APC/C). Mad2 binding to Cdc20 is a complex reaction that entails the conformati...

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Autores principales:	Marco Simonetta, Romilde Manzoni, Roberto Mosca, Marina Mapelli, Lucia Massimiliano, Martin Vink, Bela Novak, Andrea Musacchio, Andrea Ciliberto
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/dfa77e6f68c7488393590553a7ab1ca3
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spelling	oai:doaj.org-article:dfa77e6f68c7488393590553a7ab1ca32021-11-25T05:33:50ZThe influence of catalysis on mad2 activation dynamics.1544-91731545-788510.1371/journal.pbio.1000010https://doaj.org/article/dfa77e6f68c7488393590553a7ab1ca32009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19143472/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Mad2 is a key component of the spindle assembly checkpoint, a safety device ensuring faithful sister chromatid separation in mitosis. The target of Mad2 is Cdc20, an activator of the anaphase-promoting complex/cyclosome (APC/C). Mad2 binding to Cdc20 is a complex reaction that entails the conformational conversion of Mad2 from an open (O-Mad2) to a closed (C-Mad2) conformer. Previously, it has been hypothesized that the conversion of O-Mad2 is accelerated by its conformational dimerization with C-Mad2. This hypothesis, known as the Mad2-template hypothesis, is based on the unproven assumption that the natural conversion of O-Mad2 required to bind Cdc20 is slow. Here, we provide evidence for this fundamental assumption and demonstrate that conformational dimerization of Mad2 accelerates the rate of Mad2 binding to Cdc20. On the basis of our measurements, we developed a set of rate equations that deliver excellent predictions of experimental binding curves under a variety of different conditions. Our results strongly suggest that the interaction of Mad2 with Cdc20 is rate limiting for activation of the spindle checkpoint. Conformational dimerization of Mad2 is essential to accelerate Cdc20 binding, but it does not modify the equilibrium of the Mad2:Cdc20 interaction, i.e., it is purely catalytic. These results surpass previously formulated objections to the Mad2-template model and predict that the release of Mad2 from Cdc20 is an energy-driven process.Marco SimonettaRomilde ManzoniRoberto MoscaMarina MapelliLucia MassimilianoMartin VinkBela NovakAndrea MusacchioAndrea CilibertoPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 7, Iss 1, p e10 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Marco Simonetta Romilde Manzoni Roberto Mosca Marina Mapelli Lucia Massimiliano Martin Vink Bela Novak Andrea Musacchio Andrea Ciliberto The influence of catalysis on mad2 activation dynamics.
description	Mad2 is a key component of the spindle assembly checkpoint, a safety device ensuring faithful sister chromatid separation in mitosis. The target of Mad2 is Cdc20, an activator of the anaphase-promoting complex/cyclosome (APC/C). Mad2 binding to Cdc20 is a complex reaction that entails the conformational conversion of Mad2 from an open (O-Mad2) to a closed (C-Mad2) conformer. Previously, it has been hypothesized that the conversion of O-Mad2 is accelerated by its conformational dimerization with C-Mad2. This hypothesis, known as the Mad2-template hypothesis, is based on the unproven assumption that the natural conversion of O-Mad2 required to bind Cdc20 is slow. Here, we provide evidence for this fundamental assumption and demonstrate that conformational dimerization of Mad2 accelerates the rate of Mad2 binding to Cdc20. On the basis of our measurements, we developed a set of rate equations that deliver excellent predictions of experimental binding curves under a variety of different conditions. Our results strongly suggest that the interaction of Mad2 with Cdc20 is rate limiting for activation of the spindle checkpoint. Conformational dimerization of Mad2 is essential to accelerate Cdc20 binding, but it does not modify the equilibrium of the Mad2:Cdc20 interaction, i.e., it is purely catalytic. These results surpass previously formulated objections to the Mad2-template model and predict that the release of Mad2 from Cdc20 is an energy-driven process.
format	article
author	Marco Simonetta Romilde Manzoni Roberto Mosca Marina Mapelli Lucia Massimiliano Martin Vink Bela Novak Andrea Musacchio Andrea Ciliberto
author_facet	Marco Simonetta Romilde Manzoni Roberto Mosca Marina Mapelli Lucia Massimiliano Martin Vink Bela Novak Andrea Musacchio Andrea Ciliberto
author_sort	Marco Simonetta
title	The influence of catalysis on mad2 activation dynamics.
title_short	The influence of catalysis on mad2 activation dynamics.
title_full	The influence of catalysis on mad2 activation dynamics.
title_fullStr	The influence of catalysis on mad2 activation dynamics.
title_full_unstemmed	The influence of catalysis on mad2 activation dynamics.
title_sort	influence of catalysis on mad2 activation dynamics.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/dfa77e6f68c7488393590553a7ab1ca3
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_version_	1718414609559322624

The influence of catalysis on mad2 activation dynamics.

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