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Cited by 56Protein Structure and DynamicsAdvanced NMR Techniques and ApplicationsProtein Interaction Studies and Fluorescence Analysis

Conformational Recognition of an Intrinsically Disordered Protein

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Krieger, James M., Fusco, Giuliana, Lewitzky, Marc, Simister, Philip C., Marchant, Jan, Camilloni, Carlo, Feller, Stephan M., De Simone, Alfonso·2014·Biophysical Journal
DOI 10.1016/j.bpj.2014.03.004PMC PMC4008819
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Abstract

There is a growing interest in understanding the properties of intrinsically disordered proteins (IDPs); however, the characterization of these states remains an open challenge. IDPs appear to have functional roles that diverge from those of folded proteins and revolve around their ability to act as hubs for protein-protein interactions. To gain a better understanding of the modes of binding of IDPs, we combined statistical mechanics, calorimetry, and NMR spectroscopy to investigate the recognition and binding of a fragment from the disordered protein Gab2 by the growth factor receptor-bound protein 2 (Grb2), a key interaction for normal cell signaling and cancer development. Structural ensemble refinement by NMR chemical shifts, thermodynamics measurements, and analysis of point mutations indicated that the population of preexisting bound conformations in the free-state ensemble of Gab2 is an essential determinant for recognition and binding by Grb2. A key role was found for transient polyproline II (PPII) structures and extended conformations. Our findings are likely to have very general implications for the biological behavior of IDPs in light of the evidence that a large fraction of these proteins possess a specific propensity to form PPII and to adopt conformations that are more extended than the typical random-coil states.

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  • The low energetic barriers that characterize the transition between active and inactive states in intrinsically disordered proteins help shift the equilibrium toward the active state.

    “The low energetic barriers that characterize the transition between active and inactive states in intrinsically disordered proteins help shift the equilibrium toward the active state [27, 28].”

    From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [27]

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Authors
Krieger, J. M., Fusco, G., Lewitzky, M., Simister, P. C., Marchant, J., Camilloni, C., Feller, S. M., & De Simone, A.
Affiliations
  • Imperial College London (GB)
  • University of Cambridge (GB)
  • University of Oxford (GB)
ORCID
Venue
Biophysical Journal
Publisher
Elsevier BV
Published
2014-04
Volume
106
Issue
8
Pages
1771-1779
ISSN
0006-3495 (ISSN-L)
DOI
10.1016/j.bpj.2014.03.004
PMC
PMC4008819
OpenAlex
W2058532979
Cited by
56
References
67
Citations by year
2026: 2 · 2025: 3 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 12 · 2017: 7 · 2016: 3 · 2015: 9 · 2014: 6
FWCI
3.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Biophysical Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Maryland Shared Open Access Repository (USMAI Consortium) (submittedVersion)
  • Digital Repository at the University of Maryland (University of Maryland College Park)
Funders
Rosetrees Trust
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Keywords
intrinsically disordered proteins, protein-protein binding, Gab2, Grb2, polyproline II, extended conformation, binding thermodynamics, protein conformational ensembles, point mutations, signal transduction
MeSH terms
Amino Acid Sequence, Molecular Sequence Data, Peptides, Protein Binding, Point Mutation, src Homology Domains, Adaptor Proteins, Signal Transducing, Mutant Proteins, GRB2 Adaptor Protein, Molecular Dynamics Simulation, Intrinsically Disordered Proteins

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