PKID Binds to KIX Via an Unstructured Transition State with Nonnative Interactions

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2017 Dec 21

PMID 29262364

Citations 24

Authors

Liza Dahal

Tristan O C Kwan

Sarah L Shammas

Jane Clarke

Affiliations

Soon will be listed here.

Abstract

Understanding the detailed mechanism of interaction of intrinsically disordered proteins with their partners is crucial to comprehend their functions in signaling and transcription. Through its interaction with KIX, the disordered pKID region of CREB protein is central in the transcription of cAMP responsive genes, including those involved in long-term memory. Numerous simulation studies have investigated these interactions. Combined with experimental results, these can provide valuable and comprehensive understanding of the mechanisms involved. Here, we probe the transition state of this interaction experimentally through analyzing the kinetic effect of mutating both interface and solvent exposed residues in pKID. We show that very few specific interactions between pKID and KIX are required in the initial binding process. Only a small number of weak interactions are formed at the transition state, including nonnative interactions, and most of the folding occurs after the initial binding event. These properties are consistent with computational results and also the majority of experimental studies of intrinsically disordered protein coupled folding and binding in other protein systems, suggesting that these may be common features.

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References

Kurcinski M, Kolinski A, Kmiecik S . Mechanism of Folding and Binding of an Intrinsically Disordered Protein As Revealed by ab Initio Simulations. J Chem Theory Comput. 2015; 10(6):2224-31. DOI: 10.1021/ct500287c. View

Tompa P, Szasz C, Buday L . Structural disorder throws new light on moonlighting. Trends Biochem Sci. 2005; 30(9):484-9. DOI: 10.1016/j.tibs.2005.07.008. View

Kee B, Arias J, Montminy M . Adaptor-mediated recruitment of RNA polymerase II to a signal-dependent activator. J Biol Chem. 1996; 271(5):2373-5. DOI: 10.1074/jbc.271.5.2373. View

Giri R, Morrone A, Toto A, Brunori M, Gianni S . Structure of the transition state for the binding of c-Myb and KIX highlights an unexpected order for a disordered system. Proc Natl Acad Sci U S A. 2013; 110(37):14942-7. PMC: 3773806. DOI: 10.1073/pnas.1307337110. View

Babu M . The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease. Biochem Soc Trans. 2016; 44(5):1185-1200. PMC: 5095923. DOI: 10.1042/BST20160172. View

Dosnon M, Bonetti D, Morrone A, Erales J, di Silvio E, Longhi S . Demonstration of a folding after binding mechanism in the recognition between the measles virus NTAIL and X domains. ACS Chem Biol. 2014; 10(3):795-802. DOI: 10.1021/cb5008579. View

Ganguly D, Zhang W, Chen J . Electrostatically accelerated encounter and folding for facile recognition of intrinsically disordered proteins. PLoS Comput Biol. 2013; 9(11):e1003363. PMC: 3836701. DOI: 10.1371/journal.pcbi.1003363. View

Uversky V . A decade and a half of protein intrinsic disorder: biology still waits for physics. Protein Sci. 2013; 22(6):693-724. PMC: 3690711. DOI: 10.1002/pro.2261. View

Romero P, Zaidi S, Fang Y, Uversky V, Radivojac P, Oldfield C . Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc Natl Acad Sci U S A. 2006; 103(22):8390-5. PMC: 1482503. DOI: 10.1073/pnas.0507916103. View

10.

Ward J, Sodhi J, McGuffin L, Buxton B, Jones D . Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol. 2004; 337(3):635-45. DOI: 10.1016/j.jmb.2004.02.002. View

11.

De Sancho D, Best R . Modulation of an IDP binding mechanism and rates by helix propensity and non-native interactions: association of HIF1α with CBP. Mol Biosyst. 2011; 8(1):256-67. DOI: 10.1039/c1mb05252g. View

12.

Radhakrishnan I, Parker D, Dyson H, Montminy M, Wright P . Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions. Cell. 1997; 91(6):741-52. DOI: 10.1016/s0092-8674(00)80463-8. View

13.

Liu Z, Huang Y . Advantages of proteins being disordered. Protein Sci. 2014; 23(5):539-50. PMC: 4005706. DOI: 10.1002/pro.2443. View

14.

Mollica L, Bessa L, Hanoulle X, Jensen M, Blackledge M, Schneider R . Binding Mechanisms of Intrinsically Disordered Proteins: Theory, Simulation, and Experiment. Front Mol Biosci. 2016; 3:52. PMC: 5016563. DOI: 10.3389/fmolb.2016.00052. View

15.

Bomblies R, Luitz M, Zacharias M . Mechanism of pKID/KIX Association Studied by Molecular Dynamics Free Energy Simulations. J Phys Chem B. 2016; 120(33):8186-92. DOI: 10.1021/acs.jpcb.6b01792. View

16.

Dogan J, Mu X, Engstrom A, Jemth P . The transition state structure for coupled binding and folding of disordered protein domains. Sci Rep. 2013; 3:2076. PMC: 3691887. DOI: 10.1038/srep02076. View

17.

Chen J . Towards the physical basis of how intrinsic disorder mediates protein function. Arch Biochem Biophys. 2012; 524(2):123-31. DOI: 10.1016/j.abb.2012.04.024. View

18.

Toto A, Gianni S . Mutational Analysis of the Binding-Induced Folding Reaction of the Mixed-Lineage Leukemia Protein to the KIX Domain. Biochemistry. 2016; 55(28):3957-62. DOI: 10.1021/acs.biochem.6b00505. View

19.

Radhakrishnan I, Dyson H, Wright P . Conformational preferences in the Ser133-phosphorylated and non-phosphorylated forms of the kinase inducible transactivation domain of CREB. FEBS Lett. 1998; 430(3):317-22. DOI: 10.1016/s0014-5793(98)00680-2. View

20.

Shammas S, Travis A, Clarke J . Allostery within a transcription coactivator is predominantly mediated through dissociation rate constants. Proc Natl Acad Sci U S A. 2014; 111(33):12055-60. PMC: 4143058. DOI: 10.1073/pnas.1405815111. View