Articles | Volume 2, issue 1
https://doi.org/10.5194/mr-2-63-2021
© Author(s) 2021. This work is distributed under
the Creative Commons Attribution 4.0 License.
the Creative Commons Attribution 4.0 License.
Special issue:
https://doi.org/10.5194/mr-2-63-2021
© Author(s) 2021. This work is distributed under
the Creative Commons Attribution 4.0 License.
the Creative Commons Attribution 4.0 License.
Research article
| 
10 Mar 2021
Research article |
| 10 Mar 2021
| 10 Mar 2021
Fragile protein folds: sequence and environmental factors affecting the equilibrium of two interconverting, stably folded protein conformations
Xingjian Xu
Structural Biology Initiative, Advanced Science Research Center, The City University of New York (CUNY), New York, NY, USA
PhD Program in Biochemistry, The Graduate Center, CUNY, New York, NY, USA
Igor Dikiy
Structural Biology Initiative, Advanced Science Research Center, The City University of New York (CUNY), New York, NY, USA
current address: Regeneron Pharmaceuticals, Tarrytown, NY, USA
Matthew R. Evans
current address: Acclaim Physician Group, Inc. Fort Worth, TX, USA
Leandro P. Marcelino
Structural Biology Initiative, Advanced Science Research Center, The City University of New York (CUNY), New York, NY, USA
Department of Chemistry and Biochemistry, The City College of New York, New York, NY, USA
Structural Biology Initiative, Advanced Science Research Center, The City University of New York (CUNY), New York, NY, USA
Department of Chemistry and Biochemistry, The City College of New York, New York, NY, USA
Biochemistry, Chemistry and Biology PhD Programs, The Graduate Center, CUNY, New York, NY, USA
Related subject area
Field: Liquid-state NMR | Topic: Applications – biological macromolecules
NMR side-chain assignments of the Crimean–Congo hemorrhagic fever virus glycoprotein n cytosolic domain
Facilitating the structural characterisation of non-canonical amino acids in biomolecular NMR
Site-selective generation of lanthanoid binding sites on proteins using 4-fluoro-2,6-dicyanopyridine
Imatinib disassembles the regulatory core of Abelson kinase by binding to its ATP site and not by binding to its myristoyl pocket
Localising nuclear spins by pseudocontact shifts from a single tagging site
Localising individual atoms of tryptophan side chains in the metallo-β-lactamase IMP-1 by pseudocontact shifts from paramagnetic lanthanoid tags at multiple sites
Fluorine NMR study of proline-rich sequences using fluoroprolines
Analysis of conformational exchange processes using methyl-TROSY-based Hahn echo measurements of quadruple-quantum relaxation
Anomalous amide proton chemical shifts as signatures of hydrogen bonding to aromatic sidechains
Rapid assessment of Watson–Crick to Hoogsteen exchange in unlabeled DNA duplexes using high-power SELOPE imino 1H CEST
High-affinity tamoxifen analogues retain extensive positional disorder when bound to calmodulin
Structural polymorphism and substrate promiscuity of a ribosome-associated molecular chaperone
Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling
Real-time nuclear magnetic resonance spectroscopy in the study of biomolecular kinetics and dynamics
The long-standing relationship between paramagnetic NMR and iron–sulfur proteins: the mitoNEET example. An old method for new stories or the other way around?
Conformational features and ionization states of Lys side chains in a protein studied using the stereo-array isotope labeling (SAIL) method
Towards resolving the complex paramagnetic nuclear magnetic resonance (NMR) spectrum of small laccase: assignments of resonances to residue-specific nuclei
Phosphoserine for the generation of lanthanide-binding sites on proteins for paramagnetic nuclear magnetic resonance spectroscopy
Louis Brigandat, Maëlys Laux, Caroline Marteau, Laura Cole, Anja Böckmann, Lauriane Lecoq, Marie-Laure Fogeron, and Morgane Callon
Magn. Reson., 5, 95–101, https://doi.org/10.5194/mr-5-95-2024, https://doi.org/10.5194/mr-5-95-2024, 2024
Short summary
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We used NMR to sequentially assign the side-chain resonances of the cytosolic domain of glycoprotein n of the Crimean–Congo hemorrhagic fever virus. The combination of cell-free protein synthesis with high-field NMR and artificial intelligence approaches facilitated a time- and effort-efficient approach. Our results will be harnessed to study the membrane-bound form of the domain and its interactions with virulence factors, which will ultimately help to understand their role in disease.
Sarah Kuschert, Martin Stroet, Yanni Ka-Yan Chin, Anne Claire Conibear, Xinying Jia, Thomas Lee, Christian Reinhard Otto Bartling, Kristian Strømgaard, Peter Güntert, Karl Johan Rosengren, Alan Edward Mark, and Mehdi Mobli
Magn. Reson., 4, 57–72, https://doi.org/10.5194/mr-4-57-2023, https://doi.org/10.5194/mr-4-57-2023, 2023
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The 20 genetically encoded amino acids provide the basis for most proteins and peptides that make up the machinery of life. This limited repertoire is vastly expanded by the introduction of non-canonical amino acids (ncAAs). Studying the structure of protein-containing ncAAs requires new computational representations that are compatible with existing modelling software. We have developed an online tool for this to aid future structural studies of this class of complex biopolymer.
Sreelakshmi Mekkattu Tharayil, Mithun C. Mahawaththa, Akiva Feintuch, Ansis Maleckis, Sven Ullrich, Richard Morewood, Michael J. Maxwell, Thomas Huber, Christoph Nitsche, Daniella Goldfarb, and Gottfried Otting
Magn. Reson., 3, 169–182, https://doi.org/10.5194/mr-3-169-2022, https://doi.org/10.5194/mr-3-169-2022, 2022
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Having shown that tagging a protein at a single site with different lanthanoid complexes delivers outstanding structural information at a selected site of a protein (such as active sites and ligand binding sites), we now present a simple way by which different lanthanoid complexes can be assembled on a highly solvent-exposed cysteine residue. Furthermore, the chemical assembly is selective for selenocysteine, if a selenocysteine residue can be introduced into the protein of interest.
Stephan Grzesiek, Johannes Paladini, Judith Habazettl, and Rajesh Sonti
Magn. Reson., 3, 91–99, https://doi.org/10.5194/mr-3-91-2022, https://doi.org/10.5194/mr-3-91-2022, 2022
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We show here that binding of the anticancer drug imatinib to the ATP site of Abelson kinase and not binding to its allosteric site coincides with the opening of the kinase regulatory core at nanomolar concentrations. This has implications for the understanding of Abelson’s kinase regulation and activity during medication as well as for the design of new Abelson kinase inhibitors.
Henry W. Orton, Elwy H. Abdelkader, Lydia Topping, Stephen J. Butler, and Gottfried Otting
Magn. Reson., 3, 65–76, https://doi.org/10.5194/mr-3-65-2022, https://doi.org/10.5194/mr-3-65-2022, 2022
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Installing a tag containing a paramagnetic metal ion on a protein can lead to large changes (pseudocontact shifts) in the resonances observed in NMR spectra. These are easily measured and contain valuable long-range structural information. The present work shows that a single tagging site furnished with different tags can be sufficient to localise atoms in proteins with high accuracy. In fact, this strategy works almost as well as the same number of tags distributed over multiple tagging sites.
Henry W. Orton, Iresha D. Herath, Ansis Maleckis, Shereen Jabar, Monika Szabo, Bim Graham, Colum Breen, Lydia Topping, Stephen J. Butler, and Gottfried Otting
Magn. Reson., 3, 1–13, https://doi.org/10.5194/mr-3-1-2022, https://doi.org/10.5194/mr-3-1-2022, 2022
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This paper explores a method for determining the solution structure of a solvent-exposed polypeptide segment (the L3 loop), which is next to the active site of the penicillin-degrading enzyme IMP-1. Tagging three different sites on the protein with paramagnetic metal ions allowed positioning of the L3 loop with atomic resolution. It was found that the method was more robust when omitting data obtained with different metal ions if obtained with the same tag at the same tagging site.
Davy Sinnaeve, Abir Ben Bouzayene, Emile Ottoy, Gert-Jan Hofman, Eva Erdmann, Bruno Linclau, Ilya Kuprov, José C. Martins, Vladimir Torbeev, and Bruno Kieffer
Magn. Reson., 2, 795–813, https://doi.org/10.5194/mr-2-795-2021, https://doi.org/10.5194/mr-2-795-2021, 2021
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Fluorine NMR was used to study the interaction between a proline-rich peptide and a SH3 domain using 4S- and 4R-fluorinated prolines whose potential as NMR probes has not been exploited yet. We present a comprehensive study addressing several aspects to be considered when using these residues as NMR probes, including relaxation and dynamics. We show that their conformational bias may be used to modulate the kinetics of protein binding to proline-rich motifs.
Christopher A. Waudby and John Christodoulou
Magn. Reson., 2, 777–793, https://doi.org/10.5194/mr-2-777-2021, https://doi.org/10.5194/mr-2-777-2021, 2021
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We describe a suite of experiments that exploit field-dependent relaxation measurements of four-spin transitions in methyl groups to characterise chemical exchange processes and which can be used as an alternative or complement to CPMG relaxation dispersion measurements. We show that these four-spin transitions benefit from the methyl TROSY effect and so provide a unique combination of slow intrinsic relaxation and high sensitivity to chemical exchange.
Kumaran Baskaran, Colin W. Wilburn, Jonathan R. Wedell, Leonardus M. I. Koharudin, Eldon L. Ulrich, Adam D. Schuyler, Hamid R. Eghbalnia, Angela M. Gronenborn, and Jeffrey C. Hoch
Magn. Reson., 2, 765–775, https://doi.org/10.5194/mr-2-765-2021, https://doi.org/10.5194/mr-2-765-2021, 2021
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The Biological Magnetic Resonance Data Bank (BMRB) has been used to identify overall trends, for example, the relationship between chemical shift and backbone conformation. The BMRB archive has grown so that statistical outliers are sufficiently numerous to afford insights into unusual or unique structural features in proteins. We analyze amide proton chemical shift outliers to gain insights into the occurrence of hydrogen bonds between an amide NH and the p-pi cloud of aromatic sidechains.
Bei Liu, Atul Rangadurai, Honglue Shi, and Hashim M. Al-Hashimi
Magn. Reson., 2, 715–731, https://doi.org/10.5194/mr-2-715-2021, https://doi.org/10.5194/mr-2-715-2021, 2021
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There is growing interest in mapping exchange dynamics between Watson–Crick and Hoogsteen conformations across different DNA contexts. However, current methods are ill-suited for measurements at a large scale because they require isotopically enriched samples. We report that Hoogsteen dynamics can be measured on unlabeled samples using 1H CEST experiments, which have higher throughput and lower cost relative to conventional methods and also provide new insights into Hoogsteen dynamics.
Lilia Milanesi, Clare R. Trevitt, Brian Whitehead, Andrea M. Hounslow, Salvador Tomas, Laszlo L. P. Hosszu, Christopher A. Hunter, and Jonathan P. Waltho
Magn. Reson., 2, 629–642, https://doi.org/10.5194/mr-2-629-2021, https://doi.org/10.5194/mr-2-629-2021, 2021
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The overall aim of the study is to provide a basis from which to improve the ability of tamoxifen family drugs to reduce the activity of a secondary target protein, calmodulin, during tumour development. The main conclusion is that the binding of a tamoxifen analogue is quite unlike that of other anti-calmodulin compounds in that two drug molecules bring the two domains of calmodulin into close proximity, but they are not fixed in orientation relative to the protein.
Chih-Ting Huang, Yei-Chen Lai, Szu-Yun Chen, Meng-Ru Ho, Yun-Wei Chiang, and Shang-Te Danny Hsu
Magn. Reson., 2, 375–386, https://doi.org/10.5194/mr-2-375-2021, https://doi.org/10.5194/mr-2-375-2021, 2021
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Trigger factor (TF) is a conserved bacterial molecular chaperone that exists in a monomer–dimer equilibrium in solution. It binds to the ribosome as a monomer to facilitate folding of nascent polypeptide chains. We showed that dimeric TF exhibits distinct domain dynamics and conformational polymorphism and that TF contains multiple substrate binding sites that are only accessible in its monomeric form. The equilibrium of TF in different oligomeric states may serve as a regulatory mechanism.
Nestor Kamdem, Yvette Roske, Dmytro Kovalskyy, Maxim O. Platonov, Oleksii Balinskyi, Annika Kreuchwig, Jörn Saupe, Liang Fang, Anne Diehl, Peter Schmieder, Gerd Krause, Jörg Rademann, Udo Heinemann, Walter Birchmeier, and Hartmut Oschkinat
Magn. Reson., 2, 355–374, https://doi.org/10.5194/mr-2-355-2021, https://doi.org/10.5194/mr-2-355-2021, 2021
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The Wnt signalling pathway plays a major role in prevention of cancer, whereby the protein Dishevelled connects from the transmembrane receptor Frizzled to downstream effectors via its PDZ domain. Here, cycles of chemical synthesis and structural biology are applied to develop PDZ ligands that block the Frizzled–Dishevelled interaction using NMR for screening, in ligand development, and for deriving structure–activity relationships. Cellular reporter assays demonstrate their efficacy.
György Pintér, Katharina F. Hohmann, J. Tassilo Grün, Julia Wirmer-Bartoschek, Clemens Glaubitz, Boris Fürtig, and Harald Schwalbe
Magn. Reson., 2, 291–320, https://doi.org/10.5194/mr-2-291-2021, https://doi.org/10.5194/mr-2-291-2021, 2021
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The folding, refolding and misfolding of biomacromolecules including proteins, DNA and RNA is an important area of biophysical research to understand functional and disease states of a cell. NMR spectroscopy provides detailed insight, with both high time and atomic resolution. These experiments put stringent requirements on signal-to-noise for often irreversible folding reactions. The review describes methodological approaches and highlights key applications.
Francesca Camponeschi, Angelo Gallo, Mario Piccioli, and Lucia Banci
Magn. Reson., 2, 203–221, https://doi.org/10.5194/mr-2-203-2021, https://doi.org/10.5194/mr-2-203-2021, 2021
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The iron–sulfur cluster binding properties of human mitoNEET have been investigated by 1D and 2D 1H paramagnetic NMR spectroscopy. The NMR spectra of both oxidized and reduced mitoNEET are significantly different from those reported previously for other [Fe2S2] proteins. Our findings revealed the unique electronic properties of mitoNEET and suggests that the specific electronic structure of the cluster possibly drives the functional properties of different [Fe2S2] proteins.
Mitsuhiro Takeda, Yohei Miyanoiri, Tsutomu Terauchi, and Masatsune Kainosho
Magn. Reson., 2, 223–237, https://doi.org/10.5194/mr-2-223-2021, https://doi.org/10.5194/mr-2-223-2021, 2021
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Although both the hydrophobic aliphatic chain and hydrophilic ζ-amino group of the lysine side chain presumably contribute to the structures and functions of proteins, the dual nature of the lysine residue has not been fully understood yet, due to the lack of appropriate methods to acquire comprehensive information on its long consecutive methylene chain at the atomic scale. We describe herein a novel strategy to address the current situation using nuclear magnetic resonance spectroscopy.
Rubin Dasgupta, Karthick B. S. S. Gupta, Huub J. M. de Groot, and Marcellus Ubbink
Magn. Reson., 2, 15–23, https://doi.org/10.5194/mr-2-15-2021, https://doi.org/10.5194/mr-2-15-2021, 2021
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A method is demonstrated that can help in sequence-specific NMR signal assignment to nuclear spins near a strongly paramagnetic metal in an enzyme. A combination of paramagnetically tailored NMR experiments and second-shell mutagenesis was used to attribute previously observed chemical exchange processes in the active site of laccase to specific histidine ligands. The signals of nuclei close to the metal can be used as spies to unravel the role of motions in the catalytic process.
Sreelakshmi Mekkattu Tharayil, Mithun Chamikara Mahawaththa, Choy-Theng Loh, Ibidolapo Adekoya, and Gottfried Otting
Magn. Reson., 2, 1–13, https://doi.org/10.5194/mr-2-1-2021, https://doi.org/10.5194/mr-2-1-2021, 2021
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A new way is presented for creating lanthanide binding sites on proteins using site-specifically introduced phosphoserine residues. The paramagnetic effects of lanthanides generate long-range effects, which contain structural information and are readily measured by NMR spectroscopy. Excellent correlations between experimentally observed and back-calculated pseudocontact shifts attest to very good immobilization of the lanthanide ions relative to the proteins.
Cited articles
Alexander, P. A., He, Y., Chen, Y., Orban, J., and Bryan, P. N.: A minimal
sequence code for switching protein structure and function, P. Natl.
Acad. Sci. USA, 106, 21149–21154, https://doi.org/10.1073/pnas.0906408106, 2009.
Alexandrescu, A. T. and Shortle, D.: Backbone dynamics of a highly
disordered 131 residue fragment of staphylococcal nuclease, J. Mol. Biol.,
242, 527–546, 1994.
Amezcua, C. A., Harper, S. M., Rutter, J., and Gardner, K. H.: Structure and
interactions of PAS kinase N-terminal PAS domain: model for intramolecular
kinase regulation, Structure, 10, 1349–1361, https://doi.org/10.1016/s0969-2126(02)00857-2, 2002.
Anfinsen, C. B.: Principles that Govern the Folding of Protein Chains,
Science, 181, 223–230, https://doi.org/10.1126/science.181.4096.223, 1973.
Best, J. L., Amezcua, C. A., Mayr, B., Flechner, L., Murawsky, C. M.,
Emerson, B., Zor, T., Gardner, K. H., and Montminy, M.: Identification of
small-molecule antagonists that inhibit an activator: coactivator
interaction, P. Natl. Acad. Sci. USA, 101, 17622–17627,
https://doi.org/10.1073/pnas.0406374101, 2004.
Bisson, W. H., Koch, D. C., O'Donnell, E. F., Khalil, S. M., Kerkvliet, N.
I., Tanguay, R. L., Abagyan, R., and Kolluri, S. K.: Modeling of the aryl
hydrocarbon receptor (AhR) ligand binding domain and its utility in virtual
ligand screening to predict new AhR ligands, J. Med. Chem., 52, 5635–5641,
https://doi.org/10.1021/jm900199u, 2009.
Buck, M., Schwalbe, H., and Dobson, C. M.: Main-chain dynamics of a
partially folded protein: 15N NMR relaxation measurements of hen egg white
lysozyme denatured in trifluoroethanol, J. Mol. Biol., 257, 669–683,
https://doi.org/10.1006/jmbi.1996.0193, 1996.
Card, P. B., Erbel, P. J. A., and Gardner, K. H.: Structural basis of ARNT
PAS-B dimerization: use of a common beta-sheet interface for hetero- and
homodimerization, J. Mol. Biol., 353, 664–677, https://doi.org/10.1016/j.jmb.2005.08.043, 2005.
Cardoso, R., Love, R., Nilsson, C. L., Bergqvist, S., Nowlin, D., Yan, J.,
Liu, K. K.-C., Zhu, J., Chen, P., Deng, Y.-L., Dyson, H. J., Greig, M. J.,
and Brooun, A.: Identification of Cys255 in HIF-1α as a novel site
for development of covalent inhibitors of HIF-1α/ARNT PasB domain
protein–protein interaction, Protein Sci., 21, 1885–1896, https://doi.org/10.1002/pro.2172, 2012.
Chapman-Smith, A., Lutwyche, J. K., and Whitelaw, M. L.: Contribution of the
Per/Arnt/Sim (PAS) domains to DNA binding by the basic helix-loop-helix PAS
transcriptional regulators, J. Biol. Chem., 279, 5353–5362,
https://doi.org/10.1074/jbc.M310041200, 2004.
Cordes, M. H., Burton, R. E., Walsh, N. P., McKnight, C. J., and Sauer, R.
T.: An evolutionary bridge to a new protein fold, Nat. Struct. Biol., 7,
1129–1132, https://doi.org/10.1038/81985, 2000.
Dai, Z., Tonelli, M., and Markley, J. L.: Metamorphic protein IscU changes
conformation by cis-trans isomerizations of two peptidyl-prolyl peptide
bonds, Biochemistry, 51, 9595–9602, https://doi.org/10.1021/bi301413y, 2012.
Delaglio, F., Grzesiek, S., Vuister, G. W., Zhu, G., Pfeifer, J., and Bax,
A.: NMRPipe: a multidimensional spectral processing system based on UNIX
pipes, J. Biomol. NMR, 6, 277–293, 1995.
Dishman, A. F., Tyler, R. C., Fox, J. C., Kleist, A. B., Prehoda, K. E.,
Babu, M. M., Peterson, F. C., and Volkman, B. F.: Evolution of fold
switching in a metamorphic protein, Science, 371, 86–90,
https://doi.org/10.1126/science.abd8700, 2021.
Dyson, H. J.: Making Sense of Intrinsically Disordered Proteins, Biophys.
J., 110, 1013–1016, https://doi.org/10.1016/j.bpj.2016.01.030, 2016.
Eigenbrot, C., Kirchhofer, D., Dennis, M. S., Santell, L., Lazarus, R. A.,
Stamos, J., and Ultsch, M. H.: The factor VII zymogen structure reveals
reregistration of beta strands during activation, Structure, 9, 627–636,
2001.
Erbel, P. J. A., Card, P. B., Karakuzu, O., Bruick, R. K., and Gardner, K.
H.: Structural basis for PAS domain heterodimerization in the basic
helix–loop–helix-PAS transcription factor hypoxia-inducible factor, P.
Natl. Acad. Sci. USA, 100, 15504–15509, https://doi.org/10.1073/pnas.2533374100, 2003.
Evans, M. R. and Gardner, K. H.: Slow transition between two beta-strand
registers is dictated by protein unfolding, J. Am. Chem. Soc., 131,
11306–11307, https://doi.org/10.1021/ja9048338, 2009.
Evans, M. R., Card, P. B., and Gardner, K. H.: ARNT PAS-B has a fragile
native state structure with an alternative beta-sheet register nearby in
sequence space, P. Natl. Acad. Sci. USA., 106, 2617–2622,
https://doi.org/10.1073/pnas.0808270106, 2009.
Gagné, D., Azad, R., Edupuganti, U. R., Williams, J., Aramini, J. M.,
Akasaka, K., and Gardner, K. H.: Use of high pressure NMR spectroscopy to rapidly identify internal ligand-binding voids in proteins, bioRxiv, preprint, https://doi.org/10.1101/2020.08.25.267195, 2020.
Gao, X., Qin, M., Yin, P., Liang, J., Wang, J., Cao, Y., and Wang, W.:
Single-Molecule Experiments Reveal the Flexibility of a Per-ARNT-Sim Domain
and the Kinetic Partitioning in the Unfolding Pathway under Force, Biophys.
J., 102, 2149–2157, https://doi.org/10.1016/j.bpj.2012.03.042, 2012.
Gerstein, M. and Echols, N.: Exploring the range of protein flexibility,
from a structural proteomics perspective, Curr. Opin. Chem. Biol., 8, 14–19,
https://doi.org/10.1016/j.cbpa.2003.12.006, 2004.
Goldberg, J.: Structural basis for activation of ARF GTPase: mechanisms of
guanine nucleotide exchange and GTP-myristoyl switching, Cell, 95, 237–248,
1998.
Guo, Y., Partch, C. L., Key, J., Card, P. B., Pashkov, V., Patel, A.,
Bruick, R. K., Wurdak, H., and Gardner, K. H.: Regulating the ARNT/TACC3
axis: multiple approaches to manipulating protein/protein interactions with
small molecules, ACS Chem. Biol., 8, 626–635, https://doi.org/10.1021/cb300604u, 2013.
Guo, Y., Scheuermann, T. H., Partch, C. L., Tomchick, D. R., and Gardner, K.
H.: Coiled-coil coactivators play a structural role mediating interactions
in hypoxia-inducible factor heterodimerization, J. Biol. Chem., 290,
7707–7721, https://doi.org/10.1074/jbc.M114.632786, 2015.
Ha, J. H. and Loh, S. N.: Protein conformational switches: from nature to
design, Chemistry, 18, 7984–7999, https://doi.org/10.1002/chem.201200348, 2012.
Ha, J. H. and Loh, S. N.: Construction of Allosteric Protein Switches by
Alternate Frame Folding and Intermolecular Fragment Exchange, Methods Mol.
Biol., 1596, 27–41, https://doi.org/10.1007/978-1-4939-6940-1_2, 2017.
Harper, S. M., Neil, L. C., and Gardner, K. H.: Structural Basis of a
Phototropin Light Switch, Science, 301, 1541–1544, https://doi.org/10.1126/science.1086810, 2003.
Henry, J. T. and Crosson, S.: Ligand-binding PAS domains in a genomic,
cellular, and structural context, Annu. Rev. Microbiol., 65, 261–286,
https://doi.org/10.1146/annurev-micro-121809-151631, 2011.
Huang, N., Chelliah, Y., Shan, Y., Taylor, C. A., Yoo, S.-H., Partch, C.,
Green, C. B., Zhang, H., and Takahashi, J. S.: Crystal structure of the
heterodimeric CLOCK:BMAL1 transcriptional activator complex, Science, 337, 189–194, https://doi.org/10.1126/science.1222804, 2012.
Johnson, B. A.: From Raw Data to Protein Backbone Chemical Shifts Using
NMRFx Processing and NMRViewJ Analysis, Methods Mol. Biol., 1688, 257–310,
https://doi.org/10.1007/978-1-4939-7386-6_13, 2018.
Johnson, B. A. and Blevins, R. A.: NMR View: A computer program for the
visualization and analysis of NMR data, J. Biomol. NMR, 4, 603–614,
https://doi.org/10.1007/bf00404272, 1994.
Khatua, P., Ray, A. J., and Hansmann, U. H. E.: Bifurcated Hydrogen Bonds
and the Fold Switching of Lymphotactin, J. Phys. Chem. B, 124, 6555–6564,
https://doi.org/10.1021/acs.jpcb.0c04565, 2020.
Klein-Seetharaman, J., Oikawa, M., Grimshaw, S. B., Wirmer, J., Duchardt,
E., Ueda, T., Imoto, T., Smith, L. J., Dobson, C. M., and Schwalbe, H.:
Long-range interactions within a nonnative protein, Science, 295, 1719–1722,
https://doi.org/10.1126/science.1067680, 2002.
Kuloğlu, E. S., McCaslin, D. R., Markley, J. L., and Volkman, B. F.:
Structural rearrangement of human lymphotactin, a C chemokine, under
physiological solution conditions, J. Biol. Chem., 277, 17863–17870,
https://doi.org/10.1074/jbc.M200402200, 2002.
Labrecque, M. P., Prefontaine, G. G., and Beischlag, T. V.: The aryl
hydrocarbon receptor nuclear translocator (ARNT) family of proteins:
transcriptional modifiers with multi-functional protein interfaces, Curr.
Mol. Med., 13, 1047–1065, 2013.
Li, D. W., Han, L., and Huo, S.: Structural and pathway complexity of
beta-strand reorganization within aggregates of human transthyretin(105-115)
peptide, J. Phys. Chem. B, 111, 5425–5433, https://doi.org/10.1021/jp0703051, 2007.
Markley, J. L., Kim, J. H., Dai, Z., Bothe, J. R., Cai, K., Frederick, R.
O., and Tonelli, M.: Metamorphic protein IscU alternates conformations in
the course of its role as the scaffold protein for iron-sulfur cluster
biosynthesis and delivery, FEBS Lett., 587, 1172–1179,
https://doi.org/10.1016/j.febslet.2013.01.003, 2013.
Marsh, J. A., Singh, V. K., Jia, Z., and Forman-Kay, J. D.: Sensitivity of
secondary structure propensities to sequence differences between alpha- and
gamma-synuclein: implications for fibrillation, Protein Sci., 15, 2795–2804,
https://doi.org/10.1110/ps.062465306, 2006.
Murzin, A. G.: Metamorphic Proteins, Science, 320, 1725–1726,
https://doi.org/10.1126/science.1158868, 2008.
Nash, A. I., McNulty, R., Shillito, M. E., Swartz, T. E., Bogomolni, R. A.,
Luecke, H., and Gardner, K. H.: Structural basis of photosensitivity in a
bacterial light-oxygen-voltage/helix-turn-helix (LOV-HTH) DNA-binding
protein, P. Natl. Acad. Sci. USA, 108, 9449–9454,
https://doi.org/10.1073/pnas.1100262108, 2011.
Norris, M., Fetler, B., Marchant, J., and Johnson, B. A.: NMRFx Processor: a
cross-platform NMR data processing program, J. Biomol. NMR, 65, 205–216,
https://doi.org/10.1007/s10858-016-0049-6, 2016.
Panteva, M. T., Salari, R., Bhattacharjee, M., and Chong, L. T.: Direct
observations of shifts in the beta-sheet register of a protein-peptide
complex using explicit solvent simulations, Biophys. J., 100, 50–52,
https://doi.org/10.1016/j.bpj.2011.03.035, 2011.
Rivera-Cancel, G., Ko, W.-H., Tomchick, D. R., Corrêa, F., and Gardner,
K. H.: Full-length structure of a monomeric histidine kinase reveals basis
for sensory regulation, P. Natl. Acad. Sci. USA, 111, 17839–17844,
https://doi.org/10.1073/pnas.1413983111, 2014.
Scheuermann, T. H., Tomchick, D. R., Machius, M., Guo, Y., Bruick, R. K.,
and Gardner, K. H.: Artificial ligand binding within the HIF2alpha PAS-B
domain of the HIF2 transcription factor, P. Natl. Acad. Sci. USA,
106, 450–455, https://doi.org/10.1073/pnas.0808092106, 2009.
Scheuermann, T. H., Li, Q., Ma, H. W., Key, J., Zhang, L., Chen, R., Garcia,
J. A., Naidoo, J., Longgood, J., Frantz, D. E., Tambar, U. K., Gardner, K.
H., and Bruick, R. K.: Allosteric inhibition of hypoxia inducible factor-2
with small molecules, Nat. Chem. Biol., 9, 271–276, https://doi.org/10.1038/nchembio.1185, 2013.
Scheuermann, T. H., Stroud, D., Sleet, C. E., Bayeh, L., Shokri, C., Wang,
H., Caldwell, C. G., Longgood, J., MacMillan, J. B., Bruick, R. K., Gardner,
K. H., and Tambar, U. K.: Isoform-Selective and Stereoselective Inhibition
of Hypoxia Inducible Factor-2, J. Med. Chem., 58, 5930–5941,
https://doi.org/10.1021/acs.jmedchem.5b00529, 2015.
Shao, Q., Wang, J., Shi, J., and Zhu, W.: The universality of beta-hairpin
misfolding indicated by molecular dynamics simulations, J. Chem. Phys., 139,
165103, https://doi.org/10.1063/1.4826461, 2013.
Shao, Q.: Folding or misfolding: the choice of beta-hairpin, J. Phys. Chem.
B, 119, 3893–3900, https://doi.org/10.1021/jp5100654, 2015.
Sheffield, P., Garrard, S., and Derewenda, Z.: Overcoming expression and
purification problems of RhoGDI using a family of “parallel” expression
vectors, Protein Expr. Purif., 15, 34–39, https://doi.org/10.1006/prep.1998.1003, 1999.
Shen, Y., Delaglio, F., Cornilescu, G., and Bax, A.: TALOS+: a hybrid
method for predicting protein backbone torsion angles from NMR chemical
shifts, J. Biomol. NMR, 44, 213–223, https://doi.org/10.1007/s10858-009-9333-z, 2009.
Tuinstra, R. L., Peterson, F. C., Kutlesa, S., Elgin, E. S., Kron, M. A.,
and Volkman, B. F.: Interconversion between two unrelated protein folds in
the lymphotactin native state, P. Natl. Acad. Sci. USA, 105,
5057–5062, https://doi.org/10.1073/pnas.0709518105, 2008.
Tyler, R. C., Murray, N. J., Peterson, F. C., and Volkman, B. F.:
Native-state interconversion of a metamorphic protein requires global
unfolding, Biochemistry, 50, 7077–7079, https://doi.org/10.1021/bi200750k, 2011.
Volkov, O. A., Kinch, L., Ariagno, C., Deng, X., Zhong, S., Grishin, N.,
Tomchick, D. R., Chen, Z., and Phillips, M. A.: Relief of autoinhibition by
conformational switch explains enzyme activation by a catalytically dead
paralog, Elife, 5, e20198, https://doi.org/10.7554/eLife.20198, 2016.
Wright, H. T. and Scarsdale, J. N.: Structural basis for serpin inhibitor
activity, Proteins, 22, 210–225, https://doi.org/10.1002/prot.340220303, 1995.
Wu, D., Potluri, N., Lu, J., Kim, Y., and Rastinejad, F.: Structural
integration in hypoxia-inducible factors, Nature, 524, 303–308,
https://doi.org/10.1038/nature14883, 2015.
Wu, D., Su, X., Lu, J., Li, S., Hood, B. L., Vasile, S., Potluri, N., Diao,
X., Kim, Y., Khorasanizadeh, S., and Rastinejad, F.: Bidirectional
modulation of HIF-2 activity through chemical ligands, Nat. Chem. Biol., 15,
367–376, https://doi.org/10.1038/s41589-019-0234-5, 2019.
Xu, X., Gagné, D., Aramini, J. M., and Gardner, K. H.: Volume and
Compressibility Differences Between Protein Conformations Revealed by
High-Pressure NMR, Biophys. J., 120, 924–935, https://doi.org/10.1016/j.bpj.2020.12.034, 2021.
Yadid, I., Kirshenbaum, N., Sharon, M., Dym, O., and Tawfik, D. S.:
Metamorphic proteins mediate evolutionary transitions of structure, P.
Natl. Acad. Sci. USA, 107, 7287–7292, https://doi.org/10.1073/pnas.0912616107, 2010.
Zhang, O. and Forman-Kay, J. D.: Structural characterization of folded and
unfolded states of an SH3 domain in equilibrium in aqueous buffer,
Biochemistry, 34, 6784–6794, 1995.
Zhao, Y., Li, L., Wu, C., Jiang, X., Ge, B., Ren, H., and Huang, F.: Stable
folding intermediates prevent fast interconversion between the closed and
open states of Mad2 through its denatured state, Protein Eng. Des. Sel., 29,
23–29, https://doi.org/10.1093/protein/gzv056, 2016.
Short summary
While most proteins adopt one conformation, several interconvert between two or more very different structures. Knowing how sequence changes and small-molecule binding can control this behavior is essential for both understanding biology and inspiring new “molecular switches” which can control cellular pathways. This work contributes by examining these topics in the ARNT protein, showing that features of both the folded and unfolded states contribute to the interconversion process.
While most proteins adopt one conformation, several interconvert between two or more very...
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