The pierced lasso topology leptin has a bolt on dynamic domain composed by the disordered loops I and III

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Item Type:	Article
Title:	The pierced lasso topology leptin has a bolt on dynamic domain composed by the disordered loops I and III
Creators Name:	Danielsson, J., Noel, J.K., Simien, J.M., Duggan, B.M., Oliveberg, M., Onuchic, J.N., Jennings, P.A. and Haglund, E.
Abstract:	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. Despite 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 to be 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 time scales, 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 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.
Keywords:	Conformational Dynamics, NMR, Protein Folding, Obesity, Leptin
Source:	Journal of Molecular Biology
ISSN:	0022-2836
Publisher:	Elsevier / Academic Press
Volume:	432
Number:	9
Page Range:	3050-3063
Date:	17 April 2020
Official Publication:	https://doi.org/10.1016/j.jmb.2020.01.035
PubMed:	View item in PubMed

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