The Pierced Lasso Topology Leptin has a Bolt on Dynamic Domain Composed by the Disordered Loops I and III. Issue 9 (17th April 2020)

• Record Type: Journal Article
• Authors: Danielsson, Jens; Noel, Jeffrey Kenneth; Simien, Jennifer Michelle; Duggan, Brendan Michael; Oliveberg, Mikael; Onuchic, José Nelson; Jennings, Patricia Ann; Haglund, Ellinor
• Is Part Of: Journal of molecular biology. Volume 432:Issue 9(2020)
• Page Start: 3050
• Page End: 3063
• Publication Date: 2020-04-17
• Subjects: conformational dynamics -- NMR -- protein folding -- obesity -- leptin; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2020.01.035
• Languages: English
• ISSNs: 0022-2836

Abstract

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. 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. Graphical abstract: Image 1 Highlights: Leptin is an obesity-related hormone involved in energy storage and regulation. NMR data confirms that leptin adopts a four-helix bundle also in solution. Two long loops are docked onto the helix bundle by a secondary hydrophobic core. The loops and a transient helix may enable functional allosteric dynamics. The present findings may serve as a benchmark for functional studies of leptin.