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Intrinsically disordered protein
Abstract
Proteins can exist in a trinity of structures: the ordered state, the molten globule, and the random coil. The five following examples suggest that native protein structure can correspond to any of the three states (not just the ordered state) and that protein function can arise from any of the three states and their transitions. (1) In a process that likely mimics infection, fd phage converts from the ordered into the disordered molten globular state. (2) Nucleosome hyperacetylation is crucial to DNA replication and transcription; this chemical modification greatly increases the net negative charge of the nucleosome core particle. We propose that the increased charge imbalance promotes its conversion to a much less rigid form. (3) Clusterin contains an ordered domain and also a native molten globular region. The molten globular domain likely functions as a proteinaceous detergent for cell remodeling and removal of apoptotic debris. (4) In a critical signaling event, a helix in calcineurin becomes bound and surrounded by calmodulin, thereby turning on calcineurin's serine/threonine phosphatase activity. Locating the calcineurin helix within a region of disorder is essential for enabling calmodulin to surround its target upon binding. (5) Calsequestrin regulates calcium levels in the sarcoplasmic reticulum by binding approximately 50 ions/molecule. Disordered polyanion tails at the carboxy terminus bind many of these calcium ions, perhaps without adopting a unique structure. In addition to these examples, we will discuss 16 more proteins with native disorder. These disordered regions include molecular recognition domains, protein folding inhibitors, flexible linkers, entropic springs, entropic clocks, and entropic bristles. Motivated by such examples of intrinsic disorder, we are studying the relationships between amino acid sequence and order/disorder, and from this information we are predicting intrinsic order/disorder from amino acid sequence. The sequence-structure relationships indicate that disorder is an encoded property, and the predictions strongly suggest that proteins in nature are much richer in intrinsic disorder than are those in the Protein Data Bank. Recent predictions on 29 genomes indicate that proteins from eucaryotes apparently have more intrinsic disorder than those from either bacteria or archaea, with typically > 30% of eucaryotic proteins having disordered regions of length > or = 50 consecutive residues.
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“Upon binding of an IDP/IDR to a signaling partner, the free energy required to bring about the disorder-to-order transition subtracts from the interfacial, contact-free energy, resulting in a highly specific interaction that can be combined with a low net free energy of association [3, 18].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [3]
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Metadata
- Authors
- Dunker, A. K., Lawson, J. D., Brown, C. J., Williams, R. M., Romero, P., Oh, J. S., Oldfield, C. J., Campen, A. M., Ratliff, C. M., Hipps, K. W., Ausio, J., Nissen, M. S., Reeves, R., Kang, C., Kissinger, C. R., Bailey, R. W., Griswold, M. D., Chiu, W., Garner, E. C., & Obradovic, Z.
- Affiliations
- Washington State University (US)
- Pfizer (United States) (US)
- Baylor College of Medicine (US)
- Corresponding author
- Dunker, A.Keith
- ORCID
- Venue
- Journal of Molecular Graphics and Modelling
- Publisher
- Elsevier BV
- Published
- 2001-02
- Volume
- 19
- Issue
- 1
- Pages
- 26-59
- ISSN
- 1093-3263 (ISSN-L)
- OpenAlex
- W4210968583
- Cited by
- 2,272
- References
- 272
- Citations by year
- 2026: 67 · 2025: 88 · 2024: 89 · 2023: 83 · 2022: 116 · 2021: 119 · 2020: 129 · 2019: 108 · 2018: 123 · 2017: 97 · 2016: 127 · 2015: 111 · 2014: 103 · 2013: 122 · 2012: 113
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Graphics and Modelling (publishedVersion)
- Funders
- U.S. National Library of Medicine (R01-LM06916)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- intrinsically disordered proteins, molten globule, random coil, protein conformational change, clusterin, calcineurin, calmodulin, calsequestrin, flexible linkers, eukaryotic proteins, protein structure prediction
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