A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.

The stability of the repeat protein IκBα, a transcriptional inhibitor in mammalian cells, is critical in the functioning of the NF-κB signaling module implicated in an array of cellular processes, including cell growth, disease, immunity and apoptosis. Structurally, IκBα is complex, with both ordere...

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Autores principales:	Srinivasan Sivanandan, Athi N Naganathan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/4ca32e533e98449c8fa976f728445569
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spelling	oai:doaj.org-article:4ca32e533e98449c8fa976f7284455692021-11-18T05:53:16ZA disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.1553-734X1553-735810.1371/journal.pcbi.1003403https://doaj.org/article/4ca32e533e98449c8fa976f7284455692013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24367251/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The stability of the repeat protein IκBα, a transcriptional inhibitor in mammalian cells, is critical in the functioning of the NF-κB signaling module implicated in an array of cellular processes, including cell growth, disease, immunity and apoptosis. Structurally, IκBα is complex, with both ordered and disordered regions, thus posing a challenge to the available computational protocols to model its conformational behavior. Here, we introduce a simple procedure to model disorder in systems that undergo binding-induced folding that involves modulation of the contact map guided by equilibrium experimental observables in combination with an Ising-like Wako-Saitô-Muñoz-Eaton model. This one-step procedure alone is able to reproduce a variety of experimental observables, including ensemble thermodynamics (scanning calorimetry, pre-transitions, m-values) and kinetics (roll-over in chevron plot, intermediates and their identity), and is consistent with hydrogen-deuterium exchange measurements. We further capture the intricate distance-dynamics between the domains as measured by single-molecule FRET by combining the model predictions with simple polymer physics arguments. Our results reveal a unique mechanism at work in IκBα folding, wherein disorder in one domain initiates a domino-like effect partially destabilizing neighboring domains, thus highlighting the effect of symmetry-breaking at the level of primary sequences. The offshoot is a multi-state and a dynamic conformational landscape that is populated by increasingly partially folded ensembles upon destabilization. Our results provide, in a straightforward fashion, a rationale to the promiscuous binding and short intracellular half-life of IκBα evolutionarily engineered into it through repeats with variable stabilities and expand the functional repertoire of disordered regions in proteins.Srinivasan SivanandanAthi N NaganathanPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 9, Iss 12, p e1003403 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Srinivasan Sivanandan Athi N Naganathan A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.
description	The stability of the repeat protein IκBα, a transcriptional inhibitor in mammalian cells, is critical in the functioning of the NF-κB signaling module implicated in an array of cellular processes, including cell growth, disease, immunity and apoptosis. Structurally, IκBα is complex, with both ordered and disordered regions, thus posing a challenge to the available computational protocols to model its conformational behavior. Here, we introduce a simple procedure to model disorder in systems that undergo binding-induced folding that involves modulation of the contact map guided by equilibrium experimental observables in combination with an Ising-like Wako-Saitô-Muñoz-Eaton model. This one-step procedure alone is able to reproduce a variety of experimental observables, including ensemble thermodynamics (scanning calorimetry, pre-transitions, m-values) and kinetics (roll-over in chevron plot, intermediates and their identity), and is consistent with hydrogen-deuterium exchange measurements. We further capture the intricate distance-dynamics between the domains as measured by single-molecule FRET by combining the model predictions with simple polymer physics arguments. Our results reveal a unique mechanism at work in IκBα folding, wherein disorder in one domain initiates a domino-like effect partially destabilizing neighboring domains, thus highlighting the effect of symmetry-breaking at the level of primary sequences. The offshoot is a multi-state and a dynamic conformational landscape that is populated by increasingly partially folded ensembles upon destabilization. Our results provide, in a straightforward fashion, a rationale to the promiscuous binding and short intracellular half-life of IκBα evolutionarily engineered into it through repeats with variable stabilities and expand the functional repertoire of disordered regions in proteins.
format	article
author	Srinivasan Sivanandan Athi N Naganathan
author_facet	Srinivasan Sivanandan Athi N Naganathan
author_sort	Srinivasan Sivanandan
title	A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.
title_short	A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.
title_full	A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.
title_fullStr	A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.
title_full_unstemmed	A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.
title_sort	disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein iκbα.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/4ca32e533e98449c8fa976f728445569
work_keys_str_mv	AT srinivasansivanandan adisorderinduceddominolikedestabilizationmechanismgovernsthefoldingandfunctionaldynamicsoftherepeatproteinikba AT athinnaganathan adisorderinduceddominolikedestabilizationmechanismgovernsthefoldingandfunctionaldynamicsoftherepeatproteinikba AT srinivasansivanandan disorderinduceddominolikedestabilizationmechanismgovernsthefoldingandfunctionaldynamicsoftherepeatproteinikba AT athinnaganathan disorderinduceddominolikedestabilizationmechanismgovernsthefoldingandfunctionaldynamicsoftherepeatproteinikba
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A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.

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