Structures of inactive retinoblastoma protein reveal multiple mechanisms for cell cycle control.

Genes & Development
Jason R BurkeSeth M Rubin

Abstract

Cyclin-dependent kinase (Cdk) phosphorylation of the Retinoblastoma protein (Rb) drives cell proliferation through inhibition of Rb complexes with E2F transcription factors and other regulatory proteins. We present the first structures of phosphorylated Rb that reveal the mechanism of its inactivation. S608 phosphorylation orders a flexible "pocket" domain loop such that it mimics and directly blocks E2F transactivation domain (E2F(TD)) binding. T373 phosphorylation induces a global conformational change that associates the pocket and N-terminal domains (RbN). This first multidomain Rb structure demonstrates a novel role for RbN in allosterically inhibiting the E2F(TD)-pocket association and protein binding to the pocket "LxCxE" site. Together, these structures detail the regulatory mechanism for a canonical growth-repressive complex and provide a novel example of how multisite Cdk phosphorylation induces diverse structural changes to influence cell cycle signaling.

References

Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Apr 5, 1996·The Journal of Biological Chemistry·E S Knudsen, J Y Wang
May 9, 1997·The Journal of Biological Chemistry·T Zarkowska, S Mittnacht
Apr 17, 1999·Molecular and Cellular Biology·V D BrownB L Gallie
May 24, 2001·Biophysical Journal·D I SvergunM H Koch
Aug 3, 2001·Nature·S J NielsenT Kouzarides
Feb 25, 2003·Proceedings of the National Academy of Sciences of the United States of America·Bing XiaoSteven J Gamblin
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Aug 25, 2005·The Journal of Biological Chemistry·Mahavir SinghTad A Holak
Dec 22, 2005·Acta Crystallographica. Section D, Biological Crystallography·Andrew G W Leslie
Jul 25, 2008·Nature Reviews. Cancer·Deborah L Burkhart, Julien Sage
Aug 23, 2008·Nature Reviews. Molecular Cell Biology·Sander van den Heuvel, Nicholas J Dyson
Sep 5, 2008·American Journal of Physiology. Cell Physiology·Laura L GorgesJoseph J Baldassare
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jul 14, 2009·General Physiology and Biophysics·Martin PelikanMichal Hammel
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
May 29, 2010·Nucleic Acids Research·Dina Schneidman-DuhovnyAndrej Sali
Apr 15, 2011·Proteins·Eva Rose M BalogSeth M Rubin
Jun 15, 2011·Trends in Cell Biology·Amity L Manning, Nicholas J Dyson

❮ Previous
Next ❯

Citations

Apr 19, 2013·Nature Reviews. Molecular Cell Biology·Frederick A Dick, Seth M Rubin
Nov 5, 2013·Nature Structural & Molecular Biology·Mardo KõivomägiMart Loog
Nov 5, 2013·Nature Structural & Molecular Biology·Denise A McGrathSeth M Rubin
Jan 18, 2013·PLoS Computational Biology·Stefka TyanovaDmitrij Frishman
Dec 11, 2013·Journal of Experimental Botany·Bénédicte DesvoyesCrisanto Gutierrez
Mar 19, 2013·Annual Review of Biophysics·Robert P Rambo, John A Tainer
May 31, 2014·ELife·Anil M NarasimhaSteven F Dowdy
Dec 12, 2012·Trends in Biochemical Sciences·Seth M Rubin
Jul 28, 2015·Cell Reports·William C H ChaoMartin R Singleton
Feb 14, 2014·Cell Biology International·Adarsh K MayankSunil K Lal
Apr 13, 2015·Current Opinion in Structural Biology·Lucía Beatriz ChemesIgnacio Enrique Sánchez
Aug 27, 2013·Biophysical Journal·Dina Schneidman-DuhovnyAndrej Sali
Aug 26, 2014·Frontiers in Genetics·Hafumi NishiAnna R Panchenko
Nov 5, 2014·Frontiers in Plant Science·Paolo A SabelliBrian A Larkins
Aug 26, 2016·Molecular Neurobiology·Luana de Almeida-PereiraLucianne Fragel-Madeira
Aug 29, 2016·Journal of Molecular Biology·Tyler J LibanSeth M Rubin
Aug 17, 2017·International Journal of Molecular Sciences·Renier Vélez-Cruz, David G Johnson
Jan 26, 2018·Protein Engineering, Design & Selection : PEDS·Nicolás PalopoliLucía B Chemes
Nov 4, 2015·Acta Crystallographica. Section D, Biological Crystallography·Wuan Geok SawGerhard Grüber
Feb 20, 2015·Journal of Virology·Halena R VanDeusen, Robert F Kalejta
Apr 2, 2014·Molecular and Cellular Biology·Feng BaiXin-Hai Pei
Jul 23, 2014·The Journal of Biological Chemistry·Liang ZhangDavid N Arnosti
Jun 22, 2020·FEBS Letters·Betheney R Pennycook, Alexis R Barr
Jan 1, 2016·Cancers of the Head & Neck·Tim N Beck, Erica A Golemis
Aug 17, 2019·Molecular Biology and Evolution·Rima MouawadDavid N Arnosti

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.

Cell Cycle Pathways

Cell cycle is a complex process regulated by several signal transduction pathways and enzymes. Here is the latest research on regulation of cell cycle and cell cycle pathways.