A Frustrated Binding Interface for Intrinsically Disordered Proteins

Jemth, Per; Mu, Xin; Engström, Åke; Dogan, Jakob

doi:10.1074/jbc.m113.537068

Cited by 43 publications

(48 citation statements)

References 38 publications

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“…The Φ value analysis represents the only experimental method available to describe the structure of a transition state and it has been employed extensively to describe the mechanism of folding of globular proteins (62,63), and lately the coupled binding and folding of IDPs (36)(37)(38)40,48,50,59,60,(64)(65)(66)(67)(68)(69)(70)(71)(72)(73). Interestingly, it has been generally observed that Φ values tend to be between zero and one, with very few cases of unusual values (i.e.…”

Section: The Structure Of the Transition State: φ Value Analysismentioning

confidence: 99%

Templated folding of intrinsically disordered proteins

Toto

Malagrinò

Visconti

et al. 2020

Journal of Biological Chemistry

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Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed “templated folding,” whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding.

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Section: The Structure Of the Transition State: φ Value Analysismentioning

confidence: 99%

Templated folding of intrinsically disordered proteins

Toto

Malagrinò

Visconti

et al. 2020

Journal of Biological Chemistry

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“…The entries also vary in the degree of structural order. While most correspond to interactions between folded domains, the database contains entries in which structuring occurs upon binding, such as protein-peptide interactions and, in the extreme case, the ACTR/NCBD interaction in which both binding partners become ordered upon binding [32]. Indeed, the requirements of having a structure in order to be included in the data set, ipso facto biases the data, and means that there is no representation of "fuzzy" complexes in which a diffuse structural ensemble in the bound state prevents the formation of a resolvable crystal.…”

Section: A Diversity Bias and Interrelationships Within Skempimentioning

confidence: 99%

SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation

Jankauskaite

Jiménez‐García

Dapkūnas

et al. 2018

Preprint

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Motivation: Understanding the relationship between the sequence, structure, binding energy, binding kinetics and binding thermodynamics of protein-protein interactions is crucial to understanding cellular signaling, the assembly and regulation of molecular complexes, the mechanisms through which mutations lead to disease, and protein engineering. Results: We present SKEMPI 2.0, a major update to our database of binding free energy changes upon mutation for structurally resolved protein-protein interactions. This version now contains manually curated binding data for 7085 mutations, an increase of 133%, including changes in kinetics for 1844 mutations, enthalpy and entropy changes for 443 mutations, and 440 mutations which abolish detectable binding. Availability:The database is available at

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“…The binding reaction involves several steps, as evidenced from the multiple kinetic phases observed in stopped flow spectroscopy and single molecule-FRET experiments [16][17][18] . It is however not clear what all kinetic phases corresponds to and equilibrium data agree well with the major kinetic binding phase 19 in overall agreement with a two-state binding mechanism.…”

Section: Introductionmentioning

confidence: 83%

“…These binding partners include among others the transcription factors and transcriptional co-regulators p53, IRF3 and NCOA1, 2 and 3 (also called SRC, TIF2 and ACTR, respectively). The interaction between NCBD and the CBP-interacting domain (CID) from NCOA3 (ACTR) has been intensively studied with kinetic methods to elucidate details about the binding mechanism [13][14][15][16] . These protein domains interact in a coupled folding and binding reaction in which CID forms two to three helices that wrap around NCBD 10 .…”

Section: Introductionmentioning

confidence: 99%

Evolution of an interaction between disordered proteins resulted in increased heterogeneity of the binding transition state

Karlsson

Paissoni

Erkelens

et al. 2020

Preprint

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Intrinsically disordered protein (IDP) domains often have multiple binding partners. Little is known regarding molecular changes in the binding mechanism when a new interaction evolves from low to high affinity. Here we compared the degree of native contacts in the transition state of the interaction of two IDP domains, low-affinity ancestral and high-affinity human NCBD and CID. We found that the coupled binding and folding mechanism of the domains is overall similar, but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex while more heterogenous transient interactions, including electrostatic, and an increased disorder characterize the human complex. From an evolutionary perspective, adaptation to new binding partners for IDPs may benefit from this ability to exploit multiple alternative transient interactions while retaining the overall pathway.

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A Frustrated Binding Interface for Intrinsically Disordered Proteins

Cited by 43 publications

References 38 publications

Templated folding of intrinsically disordered proteins

Templated folding of intrinsically disordered proteins

SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation

Evolution of an interaction between disordered proteins resulted in increased heterogeneity of the binding transition state

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