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The Pierced Lasso Topology Leptin has a Bolt on Dynamic Domain Composed by the Disordered Loops I and III
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 82020 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 432, no 9, p. 3050-3063Article in journal (Refereed) Published
Abstract [en]

Leptin is an important signaling hormone, mostly known for its role in energy expenditure and satiety. Furthermore, leptin plays a major role in other proteinopathies, such as cancer, marked hyperphagia, impaired immune function, and inflammation. In spite of its biological relevance in human health, there are no NMR resonance assignments of the human protein available, obscuring high-resolution characterization of the soluble protein and/or its conformational dynamics, suggested as being important for receptor interaction and biological activity. Here, we report the nearly complete backbone resonance assignments of human leptin. Chemical shift-based secondary structure prediction confirms that in solution leptin forms a four-helix bundle including a pierced lasso topology. The conformational dynamics, determined on several timescales, show that leptin is monomeric, has a rigid four-helix scaffold, and a dynamic domain, including a transiently formed helix. The dynamic domain is anchored to the helical scaffold by a secondary hydrophobic core, pinning down the long loops of leptin to the protein body, inducing motional restriction without a well-defined secondary or tertiary hydrogen bond stabilized structure. This dynamic region is well suited for and may be involved in functional allosteric dynamics upon receptor binding.

Place, publisher, year, edition, pages
2020. Vol. 432, no 9, p. 3050-3063
Keywords [en]
conformational dynamics, NMR, protein folding, obesity, leptin
National Category
Biological Sciences Chemical Sciences
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URN: urn:nbn:se:su:diva-183157DOI: 10.1016/j.jmb.2020.01.035ISI: 000534598900014PubMedID: 32081588OAI: oai:DiVA.org:su-183157DiVA, id: diva2:1450657
Available from: 2020-07-01 Created: 2020-07-01 Last updated: 2022-02-26Bibliographically approved

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Danielsson, JensDuggan, Brendan MichaelOliveberg, Mikael

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