Cited by 223Protein Structure and DynamicsReceptor Mechanisms and SignalingProtein Kinase Regulation and GTPase Signaling

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Dynamic Allostery: Linkers Are Not Merely Flexible

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Ma, Buyong, Tsai, Chung-Jung, Haliloğlu, Türkan, Nussinov, Ruth·2011·Structure

DOI 10.1016/j.str.2011.06.002PMC PMC6361528

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Abstract

Most proteins consist of multiple domains. How do linkers efficiently transfer information between sites that are on different domains to activate the protein? Mere flexibility only implies that the conformations would be sampled. For fast timescales between triggering events and cellular response, which often involves large conformational change, flexibility on its own may not constitute a good solution. We posit that successive conformational states along major allosteric propagation pathways are pre-encoded in linker sequences where each state is encoded by the previous one. The barriers between these states that are hierarchically populated are lower, achieving faster timescales even for large conformational changes. We further propose that evolution has optimized the linker sequences and lengths for efficiency, which explains why mutations in linkers may affect protein function and review the literature in this light.

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Authors: Ma, B., Tsai, C.-J., Haliloğlu, T., & Nussinov, R.
Affiliations: National Cancer Institute (US)
Tel Aviv University (IL)
Corresponding author: Nussinov, Ruth
ORCID: Ma, Buyong
Tsai, Chung-Jung
Nussinov, Ruth
Venue: Structure
Publisher: Elsevier BV
Published: 2011-07
Volume: 19
Issue: 7
Pages: 907-917
ISSN: 0969-2126 (ISSN-L)
DOI: 10.1016/j.str.2011.06.002
PMC: PMC6361528
OpenAlex: W2112600835
Cited by: 222
References: 119
Citations by year: 2026: 6 · 2025: 8 · 2024: 6 · 2023: 8 · 2022: 10 · 2021: 15 · 2020: 10 · 2019: 15 · 2018: 10 · 2017: 12 · 2016: 17 · 2015: 29 · 2014: 24 · 2013: 23 · 2012: 19
FWCI: 2.18
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 747 d)
Locations: Structure (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Health and Human Services
Türkiye Bilimler Akademisi
National Institutes of Health (HHSN261200800001C)
National Cancer Institute (HHSN261200800001E))
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: dynamic allostery, protein linkers, protein domains, conformational change, protein activation
MeSH terms: Allosteric Regulation, Allosteric Site, Animals, Binding Sites, Humans, Models, Molecular, Plants, Protein Binding, Proteins, Thermodynamics, Signal Transduction, Protein Structure, Tertiary, Protein Subunits

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Dynamic Allostery: Linkers Are Not Merely Flexible

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