Insights into Coupled Folding and Binding Mechanisms from Kinetic Studies

Shammas, Sarah L.; Crabtree, Michael D.; Dahal, Liza; Wicky, Basile I. M.; Clarke, Jane

doi:10.1074/jbc.r115.692715

Cited by 146 publications

(238 citation statements)

References 62 publications

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“…55; 56 There has been much recent interest in classifying binding mechanisms of intrinsically disordered proteins and domains (for recent reviews on the subject, see references 57 and 58). 57; 58 Conformational selection would require adoption of the bound-state conformation in the disordered ensemble, and examples of this binding mechanism typically have a significant population of the disordered state in a binding-ready conformation. 59 However, current experimental evidence suggests that TnI C 186–210 (the region containing putative thin filament binding sites) is dynamic and lacking secondary structure in a large population of the conformational ensemble.…”

Section: Coupled Binding and Folding Of Tnic: Evidence And Potentialmentioning

confidence: 99%

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Order–Disorder Transitions in the Cardiac Troponin Complex

Metskas

Rhoades

2016

Journal of Molecular Biology

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The troponin complex is a molecular switch that ties shifting intracellular calcium concentration to association and dissociation of actin and myosin, effectively allowing excitation-contraction coupling in striated muscle. Although there is a long history of muscle biophysics and structural biology, many of the mechanistic details that enable troponin’s function remain incompletely understood. This review summarizes the current structural understanding of the troponin complex on the muscle thin filament, focusing on conformational changes in flexible regions of the troponin I subunit. In particular, we focus on order-disorder transitions in the C-terminal domain of troponin I, which have important implications in cardiac disease, and could also have potential as a model system for the study of coupled binding and folding.

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Section: Coupled Binding and Folding Of Tnic: Evidence And Potentialmentioning

confidence: 99%

“…Therefore, this section concentrates on the induced fit and mixed mechanisms, which are likely the favored interaction mechanisms for association of disordered regions with their binding targets. 58 …”

Section: Coupled Binding and Folding Of Tnic: Evidence And Potentialmentioning

confidence: 99%

Order–Disorder Transitions in the Cardiac Troponin Complex

Metskas

Rhoades

2016

Journal of Molecular Biology

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“…Of course, this is an artificial and simple system compared to the crowded nature of the cell where numerous competing interactions are possible with a diversity of cellular components. Finally, interaction and binding of the intermediately folded target protein with the sHsp during chaperone action, and its subsequent refolding, would couple folding to binding (Ganguly and Chen 2011;Shammas et al 2016). Thereby, sHsps, either as individuals or in partnership with each other and other molecular chaperones (the latter potentially also utilising ATP hydrolysis), would contribute to the maintenance of cellular proteostasis (Jeng et al 2015).…”

Section: Introductionmentioning

confidence: 99%

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

Carver

Grosas

Ecroyd

et al. 2017

Cell Stress and Chaperones

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Small heat-shock proteins (sHsps), such as αB-crystallin, are one of the major classes of molecular chaperone proteins. In vivo, under conditions of cellular stress, sHsps are the principal defence proteins that prevent large-scale protein aggregation. Progress in determining the structure of sHsps has been significant recently, particularly in relation to the conserved, central and β-sheet structured α-crystallin domain (ACD). However, an understanding of the structure and functional roles of the N-and C-terminal flanking regions has proved elusive mainly because of their unstructured and dynamic nature. In this paper, we propose functional roles for both flanking regions, based around three properties: (i) they act in a localised crowding manner to regulate interactions with target proteins during chaperone action, (ii) they protect the ACD from deleterious amyloid fibril formation and (iii) the flexibility of these regions, particularly at the extreme C-terminus in mammalian sHsps, provides solubility for sHsps under chaperone and nonchaperone conditions. In the eye lens, these properties are highly relevant as the crystallin proteins, in particular the two sHsps αA-and αB-crystallin, are present at very high concentrations.

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“…The utility of kinetic approaches for illuminating the mechanism of coupled folding and binding of IDPs is the subject of the second article in the series by Clarke and co-workers (2). Charged residues are overrepresented in IDPs, which can be exacerbated by their propensity for PTMs such as phosphorylation.…”

Section: How Are Idpsmentioning

confidence: 99%

“…: 734-615-5238; E-mail: rbanerje@umich.edu. 2 The abbreviations used are: IDP, intrinsically disordered protein; PTM, posttranslational modification; CBP, CREB-binding protein; CREB, cAMP-response element-binding protein. …”

mentioning

confidence: 99%

Introduction to the Thematic Minireview Series on Intrinsically Disordered Proteins

Banerjee

2016

Journal of Biological Chemistry

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In this thematic minireview series, the JBC presents six exciting articles on low complexity or intrinsically disordered proteins (IDPs). The dynamical and fluctuating structures of IDPs or of disordered regions within proteins result in virtually all of their primary sequence being exposed, at least at some time, to potential interacting partners. Their structural versatility underlies their often wide functional repertoires, which is further expanded by post-translational modifications. Given these characteristics, it is not surprising that IDPs serve as important hubs in signaling networks, scaffolding multivalent interactions. They are also important for organizing membrane-less protein organelles. This collection of reviews discusses biophysical approaches for studying IDPs and illuminates their importance to critical functions such as cell cycle control, transcription, and translation, as well as their regulation via cellular input signals. How are IDPs2 or protein regions scripted in primary sequence space? In the first article in this series, Uversky notes that the sequence space of IDPs is typified by a low content of hydrophobic amino acid residues and high content of uncompensated charges (1). Missing an innate folding code, IDPs rely on binding partners to confer structural order, which, depending on the ligand, can lead to differently folded structures. Posttranslational modifications (PTMs) represent yet another strategy for modulating IDPs. Moreover, functionally significant structural transitions can involve differently disordered forms. Hence, the potential multiplicity of form and function in IDPs defies the conventional one structure-one function notion. In fact, many hub proteins that link protein-protein interaction networks and integrate signals are IDPs exemplifying the importance of dynamic structural remodeling for supporting a range of functions. The review ends with provocative ideas about the evolution of IDPs, which are more prevalent in complex organisms and are often encoded by regions of mRNA affected by alternative splicing.The utility of kinetic approaches for illuminating the mechanism of coupled folding and binding of IDPs is the subject of the second article in the series by Clarke and co-workers (2). Charged residues are overrepresented in IDPs, which can be exacerbated by their propensity for PTMs such as phosphorylation. Hence, electrostatic steering is considered to be important for enhancing coupled folding and binding of IDPs. Kinetic studies are also important for addressing the chicken and egg question of whether binding (in which folding is induced upon binding) or folding (in which only a select conformer from the ensemble can bind) comes first. Finally, the authors discuss how the combination of mutagenesis and kinetic studies can allow the molecular interactions in the transition state between IDPs and their partners to be mapped.In the third article in the series, Bah and Forman-Kay discuss modulation of IDP function by PTMs (3). The structural and therefore func...

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Insights into Coupled Folding and Binding Mechanisms from Kinetic Studies

Cited by 146 publications

References 62 publications

Order–Disorder Transitions in the Cardiac Troponin Complex

Order–Disorder Transitions in the Cardiac Troponin Complex

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

Introduction to the Thematic Minireview Series on Intrinsically Disordered Proteins

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