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Cited by 97Protein Structure and DynamicsEnzyme Structure and FunctionRNA and protein synthesis mechanisms

Folding funnels and conformational transitions via hinge-bending motions

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Kumar, Sandeep, Ma, Buyong, Tsai, Chung-Jung, Wolfson, Haim, Nussinov, Ruth·1999·Cell Biochemistry and Biophysics
DOI 10.1007/bf02738169
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Abstract

In this article we focus on presenting a broad range of examples illustrating low-energy transitions via hinge-bending motions. The examples are divided according to the type of hinge-bending involved; namely, motions involving fragments of the protein chains, hinge-bending motions involving protein domains, and hinge-bending motions between the covalently unconnected subunits. We further make a distinction between allosterically and nonallosterically regulated proteins. These transitions are discussed within the general framework of folding and binding funnels. We propose that the conformers manifesting such swiveling motions are not the outcome of "induced fit" binding mechanism; instead, molecules exist in an ensemble of conformations that are in equilibrium in solution. These ensembles, which populate the bottoms of the funnels, a priori contain both the "open" and the "closed" conformational isomers. Furthermore, we argue that there are no fundamental differences among the physical principles behind the folding and binding funnels. Hence, there is no basic difference between funnels depicting ensembles of conformers of single molecules with fragment, or domain motions, as compared to subunits in multimeric quaternary structures, also showing such conformational transitions. The difference relates only to the size and complexity of the system. The larger the system, the more complex its corresponding fused funnel(s). In particular, funnels associated with allosterically regulated proteins are expected to be more complicated, because allostery is frequently involved with movements between subunits, and consequently is often observed in multichain and multimolecular complexes. This review centers on the critical role played by flexibility and conformational fluctuations in enzyme activity. Internal motions that extend over different time scales and with different amplitudes are known to be essential for the catalytic cycle. The conformational change observed in enzyme-substrate complexes as compared to the unbound enzyme state, and in particular the hinge-bending motions observed in enzymes with two domains, have a substantial effect on the enzymatic catalytic activity. The examples we review span the lipolytic enzymes that are particularly interesting, owing to their activation at the water-oil interface; an allosterically controlled dehydrogenase (lactate dehydrogenase); a DNA methyltransferase, with a covalently-bound intermediate; large-scale flexible loop motions in a glycolytic enzyme (TIM); domain motion in PGK, an enzyme which is essential in most cells, both for ATP generation in aerobes and for fermentation in anaerobes; adenylate kinase, showing large conformational changes, owing to their need to shield their catalytic centers from water; a calcium-binding protein (calmodulin), involved in a wide range of cellular calcium-dependent signaling; diphtheria toxin, whose large domain motion has been shown to yield "domain swapping;" the hexameric glutamate dehydrogenase, which has been studied both in a thermophile and in a mesophile; an allosteric enzyme, showing subunit motion between the R and the T states (aspartate transcarbamoylase), and the historically well-studied lac repressor. Nonallosteric subunit transitions are also addressed, with some examples (aspartate receptor and BamHI endonuclease). Hence, using this enzyme-catalysis-centered discussion, we address energy funnel landscapes of large-scale conformational transitions, rather than the faster, quasi-harmonic, thermal fluctuations.

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Authors
Kumar, S., Ma, B., Tsai, C.-J., Wolfson, H., & Nussinov, R.
Affiliations
  • National Cancer Institute (US)
  • Frederick National Laboratory for Cancer Research (US)
  • Tel Aviv University (IL)
Corresponding author
Nussinov, Ruth
ORCID
Venue
Cell Biochemistry and Biophysics
Publisher
Springer Science and Business Media LLC
Published
1999-06
Volume
31
Issue
2
Pages
141-164
ISSN
  • 1085-9195 (ISSN-L)
  • 1559-0283
DOI
10.1007/bf02738169
OpenAlex
W2061090993
Cited by
94
References
72
Citations by year
2026: 3 · 2025: 5 · 2024: 1 · 2023: 8 · 2022: 5 · 2021: 5 · 2020: 2 · 2019: 4 · 2018: 1 · 2017: 1 · 2016: 6 · 2015: 2 · 2014: 1 · 2013: 4 · 2012: 6
FWCI
0.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Biochemistry and Biophysics (publishedVersion)
  • PubMed (publishedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, public-domain)
Funders
  • National Institutes of Health (n01co056000-057)
  • National Cancer Institute (N01 CO 56000)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
folding funnel, hinge-bending motion, protein conformational change, allosteric regulation, induced fit, conformational ensembles, protein flexibility, enzyme activity, lipolytic enzymes, oil-water interface, lactate dehydrogenase, DNA methyltransferases, TIM barrel, phosphoglycerate kinase, adenylate kinase
MeSH terms
Adenylate Kinase, Aspartate Carbamoyltransferase, Calmodulin, Diphtheria Toxin, Glutamate Dehydrogenase, L-Lactate Dehydrogenase, Lipase, Models, Biological, Models, Molecular, Phosphoglycerate Kinase, Protein Binding, Protein Conformation, Repressor Proteins, Triose-Phosphate Isomerase, Deoxyribonuclease BamHI, DNA-Cytosine Methylases, Receptors, Amino Acid, Protein Folding, Chaperonin 60

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