Composite low affinity interactions dictate recognition of the cyclin-dependent kinase inhibitor Sic1 by the SCFCdc4 ubiquitin ligase.

Proceedings of the National Academy of Sciences of the United States of America
Xiaojing TangMike Tyers

Abstract

The ubiquitin ligase SCF(Cdc4) (Skp1/Cul1/F-box protein) recognizes its substrate, the cyclin-dependent kinase inhibitor Sic1, in a multisite phosphorylation-dependent manner. Although short diphosphorylated peptides derived from Sic1 can bind to Cdc4 with high affinity, through systematic mutagenesis and quantitative biophysical analysis we show that individually weak, dispersed Sic1 phospho sites engage Cdc4 in a dynamic equilibrium. The affinities of individual phosphoepitopes serve to tune the overall phosphorylation site threshold needed for efficient recognition. Notably, phosphoepitope affinity for Cdc4 is dramatically weakened in the context of full-length Sic1, demonstrating the importance of regional environment on binding interactions. The multisite nature of the Sic1-Cdc4 interaction confers cooperative dependence on kinase activity for Sic1 recognition and ubiquitination under equilibrium reaction conditions. Composite dynamic interactions of low affinity sites may be a general mechanism to establish phosphorylation thresholds in biological responses.

References

Feb 16, 1995·Nature·T Pawson
Oct 11, 2003·Molecular Cell·Markus WelckerJames M Roberts
Feb 13, 2004·Nucleic Acids Research·Lilia M IakouchevaA Keith Dunker
Jun 9, 2004·Current Biology : CB·Kenneth H MobergIswar K Hariharan
Feb 3, 2005·Nature Reviews. Molecular Cell Biology·Matthew D Petroski, Raymond J Deshaies
May 25, 2007·Proceedings of the National Academy of Sciences of the United States of America·Mikael BorgHue Sun Chan
Nov 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Tanja MittagJulie D Forman-Kay
May 23, 2009·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Eszter Hazy, Peter Tompa
Jul 9, 2009·Journal of Molecular Recognition : JMR·Tanja MittagJulie D Forman-Kay
Sep 12, 2009·Trends in Biochemical Sciences·Toby J Gibson
Oct 21, 2009·Nature Chemical Biology·David D BoehrPeter E Wright
Apr 20, 2010·Nature·Mohan K MalleshaiahStephen W Michnick

❮ Previous
Next ❯

Citations

Feb 2, 2013·Biochemistry·Paul J BarrettCharles R Sanders
Oct 5, 2013·Journal of Medicinal Chemistry·Zhou YinAaron J Oakley
May 10, 2013·Nature Reviews. Molecular Cell Biology·Jeffrey R SkaarMichele Pagano
Jan 15, 2013·Nature Structural & Molecular Biology·Nicholas A LyonsDavid O Morgan
May 16, 2013·Database : the Journal of Biological Databases and Curation·Ivan SadowskiMike Tyers
Mar 29, 2014·The Journal of Physical Chemistry. B·Baoxu LiuClaudiu C Gradinaru
Apr 10, 2014·Proceedings of the National Academy of Sciences of the United States of America·Ellen R EdenbergDavid P Toczyski
Dec 4, 2013·Genes & Development·Markus WelckerBruce E Clurman
Oct 27, 2015·Current Opinion in Structural Biology·Olwyn Byron, Bente Vestergaard
Sep 24, 2014·Proceedings of the National Academy of Sciences of the United States of America·Peter M HwangBrian D Sykes
Dec 27, 2015·Trends in Biochemical Sciences·Prasad Trivedi, P Todd Stukenberg
Mar 1, 2016·Chemical Reviews·Veronika CsizmokJulie D Forman-Kay
Oct 15, 2013·Journal of Molecular Biology·Amanda Nourse, Tanja Mittag
Oct 7, 2015·Trends in Biochemical Sciences·James W Dennis
Jul 15, 2015·Biochemistry·Kevin G MarkDavid P Toczyski
Jan 23, 2014·Proceedings of the National Academy of Sciences of the United States of America·Canan KuscuLeemor Joshua-Tor
May 29, 2012·Structure·Wesley J ErringtonGilbert G Privé
Jan 15, 2015·Science Signaling·Justin G EnglishHenrik G Dohlman
Mar 28, 2017·PLoS Computational Biology·Matthew J BettsRobert B Russell
May 26, 2017·Journal of Chemical Information and Modeling·S Roy KimuraAngelo D Favia
Jan 4, 2017·Nature Communications·Veronika CsizmokJulie D Forman-Kay
Jan 18, 2017·FEBS Open Bio·Inma Quilis, J Carlos Igual
May 13, 2017·Cell Discovery·Marta Moreno-TorresClaudio De Virgilio
Nov 30, 2019·Proceedings of the National Academy of Sciences of the United States of America·Wesley J ErringtonCasim A Sarkar
Mar 22, 2014·The Journal of Biological Chemistry·Neda DelgoshaieAlain Verreault
Jul 22, 2021·Computational and Structural Biotechnology Journal·Ilinka ClercJuan Cortés
Aug 28, 2014·Journal of the American Chemical Society·Benoît GigantGuy Lippens
Jun 6, 2014·Chemical Reviews·Francois-Xavier TheilletPhilipp Selenko
Oct 6, 2021·Open Biology·Owen Michael MorrisRivka Leah Isaacson

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.