Determinants of conformational dimerization of Mad2 and its inhibition by p31comet

The EMBO Journal
Marina MapelliAndrea Musacchio


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 p31comet (formerly CMT2). Upon binding Cdc20, Mad2 changes its conformation from O-Mad2 (Open) to C-Mad2 (Closed). A Mad1-bound C-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 p31com...Continue Reading


Sep 1, 1992·Genes & Development·C B Epstein, F R Cross
Aug 9, 1991·Cell·R Li, Andrew W Murray
Mar 7, 1998·Science·L H HwangAndrew W Murray
Sep 16, 1998·Proceedings of the National Academy of Sciences of the United States of America·Katja Wassmann, Robert Benezra
Oct 24, 1998·The Journal of Cell Biology·R H ChenAndrew W Murray
Aug 6, 1999·Molecular Biology of the Cell·R H ChenKevin G Hardwick
Mar 4, 2000·Nature Structural Biology·Xuelian LuoG Wagner
Mar 8, 2000·The Journal of Cell Biology·Kevin G HardwickAndrew W Murray
May 15, 2002·Molecular Biology of the Cell·Eunah Chung, Rey-Huei Chen
Jun 21, 2002·Methods in Enzymology·Fred Sherman
Jul 3, 2002·The Journal of Cell Biology·Qi ChenDavid Schubert
Oct 3, 2002·Nature Reviews. Molecular Cell Biology·Andrea Musacchio, Kevin G Hardwick
Oct 22, 2002·Molecular Biology of the Cell·Katie B ShannonEdward D Salmon
Nov 29, 2002·The EMBO Journal·Toshiyuki HabuTomohiro Matsumoto
Feb 8, 2003·The EMBO Journal·Katja WassmannRobert Benezra
Mar 17, 2004·Oncogene·Rajnish Bharadwaj, Hongtao Yu
Mar 17, 2004·Nature Structural & Molecular Biology·Xuelian LuoHongtao Yu
Feb 8, 2005·Current Biology : CB·Anna De AntoniAndrea Musacchio
Feb 23, 2005·Current Biology : CB·Kevin G Hardwick
Mar 31, 2005·Cell·Kim Nasmyth
Apr 1, 2005·Nature·Robert S Hagan, Peter K Sorger
May 18, 2005·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Anna DeAntoniAndrea Musacchio
Jul 28, 2005·Journal of Cell Science·Christopher J MorrowStephen S Taylor
Aug 9, 2005·Trends in Cell Biology·Benjamin A Pinsky, Sue Biggins
Oct 11, 2005·Trends in Cell Biology·Gordon K ChanTim Yen


Apr 20, 2013·Trends in Biochemical Sciences·Luying JiaHongtao Yu
Oct 5, 2011·Nature Cell Biology·Andrew W Murray
Apr 12, 2007·Nature Reviews. Molecular Cell Biology·Andrea Musacchio, Edward D Salmon
Dec 22, 2012·Nature Reviews. Molecular Cell Biology·Emily A Foley, Tarun M Kapoor
Feb 9, 2011·Proceedings of the National Academy of Sciences of the United States of America·Adar TeichnerAvram Hershko
Mar 20, 2013·Proceedings of the National Academy of Sciences of the United States of America·Christine C JaoJames H Hurley
Apr 2, 2011·The Journal of Biological Chemistry·Somsubhra NathSusanta Roychoudhury
Apr 29, 2011·The Journal of Biological Chemistry·Aaron R TiptonSong-Tao Liu
May 1, 2012·The Journal of Biological Chemistry·Hoi Tang MaRandy Y C Poon
Oct 4, 2011·Molecular Biology of the Cell·Robert S HaganPeter K Sorger
Nov 16, 2011·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Andrea Musacchio
Jul 9, 2009·Cell Division·Evan C OsmundsonHiroaki Kiyokawa
Nov 22, 2011·Journal of Cell Science·Frederick G WesthorpeStephen S Taylor
Jan 16, 2009·PLoS Biology·Marco SimonettaAndrea Ciliberto
Feb 7, 2008·PloS One·Bashar IbrahimPeter Dittrich
Apr 3, 2014·International Journal of Molecular Sciences·Chaoqun LiGuangju Chen
Nov 3, 2010·Proceedings of the National Academy of Sciences of the United States of America·Soonjoung KimHongtao Yu
Oct 27, 2006·Proceedings of the National Academy of Sciences of the United States of America·Richard P Sear, Martin Howard
Mar 19, 2013·Annual Review of Biochemistry·Leonardo K Teixeira, Steven I Reed
Aug 6, 2014·Proceedings of the National Academy of Sciences of the United States of America·Esther EytanAvram Hershko
Apr 17, 2013·The Journal of Cell Biology·Ivana Primorac, Andrea Musacchio
Nov 26, 2008·The Journal of Cell Biology·John J SkinnerBen E Black
Oct 13, 2010·The Journal of Cell Biology·Nannette JellumaGeert J P L Kops
Jun 11, 2008·The Journal of Cell Biology·Anthony TigheStephen S Taylor
Jan 26, 2011·Critical Reviews in Biochemistry and Molecular Biology·Janel R McLeanKathleen L Gould
Aug 26, 2015·Proceedings of the National Academy of Sciences of the United States of America·Mayuko HaraXuelian Luo
Mar 29, 2011·Seminars in Cell & Developmental Biology·Soonjoung Kim, Hongtao Yu
Oct 21, 2015·Current Biology : CB·Andrea Musacchio
May 13, 2008·Biochimica Et Biophysica Acta·Saskia J E Suijkerbuijk, Geert J P L Kops
Nov 25, 2015·The Journal of Cell Biology·Scott C Rosenberg, Kevin D Corbett
Jul 25, 2009·The EMBO Journal·Andrea Ciliberto, Jagesh V Shah
Jul 21, 2011·The EMBO Journal·Luca L FavaAnna Santamaria
Jun 15, 2011·The EMBO Journal·Michael OrthOlaf Stemmann
Oct 7, 2015·The Journal of Cell Biology·Hao JiangYixian Zheng
Feb 28, 2008·Current Biology : CB·Jan-Michael Peters
Nov 24, 2012·Current Biology : CB·Pablo Lara-GonzalezStephen S Taylor
Dec 14, 2011·Molecular Cell·Gianluca VarettiAndrea Musacchio
Nov 21, 2007·Cell·Maojun YangXuelian Luo
Nov 13, 2008·Structure·Xuelian Luo, Hongtao Yu
Jan 22, 2015·Nature Reviews. Molecular Cell Biology·Sushama Sivakumar, Gary J Gorbsky
Oct 9, 2007·Current Opinion in Structural Biology·Marina Mapelli, Andrea Musacchio
Jan 20, 2017·Nature·Alex C FaesenAndrea Musacchio
Jun 1, 2017·Cell Reports·Daniel Henry MarksRobert Benezra
Sep 11, 2018·PLoS Computational Biology·Fridolin GrossAndrea Ciliberto
Jul 16, 2014·The EMBO Journal·Laura A Díaz-MartínezHongtao Yu
Feb 21, 2018·EMBO Reports·Manuel HaschkaAndreas Villunger
Dec 2, 2010·Biochemical Society Transactions·Valentina RossioSimonetta Piatti
Jun 22, 2017·Scientific Reports·Richard HenzeBashar Ibrahim
Jun 6, 2019·F1000Research·Hiroyuki Yamano
Jan 1, 2016·AIMS Molecular Science·Song-Tao Liu, Hang Zhang
Mar 12, 2009·Molecular Cancer Research : MCR·Miyong YunKee-Ho Lee
Jan 2, 2021·Science·Valentina PianoAndrea Musacchio

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