Integrating solid-state NMR and computational modeling to investigate the structure and dynamics of membrane-associated ghrelin
Autor: | Jens Meiler, Daniel Huster, Constance Chollet, Stephanie H. DeLuca, Gerrit Vortmeier, Annette G. Beck-Sickinger, Sylvia Els-Heindl, Holger A. Scheidt |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
Models
Molecular Protein Conformation Growth hormone secretagogue receptor lcsh:Medicine Peptide 010402 general chemistry 01 natural sciences Cell membrane 03 medical and health sciences Protein structure medicine Humans lcsh:Science Nuclear Magnetic Resonance Biomolecular Protein secondary structure 030304 developmental biology Polyproline helix chemistry.chemical_classification 0303 health sciences Multidisciplinary Chemistry Cell Membrane digestive oral and skin physiology lcsh:R Computational Biology Nuclear magnetic resonance spectroscopy Ghrelin 0104 chemical sciences medicine.anatomical_structure Biochemistry Biophysics lcsh:Q Research Article |
Zdroj: | PLoS ONE, Vol 10, Iss 3, p e0122444 (2015) PLoS ONE |
ISSN: | 1932-6203 |
Popis: | The peptide hormone ghrelin activates the growth hormone secretagogue receptor 1a, also known as the ghrelin receptor. This 28-residue peptide is acylated at Ser3 and is the only peptide hormone in the human body that is lipid-modified by an octanoyl group. Little is known about the structure and dynamics of membrane-associated ghrelin. We carried out solid-state NMR studies of ghrelin in lipid vesicles, followed by computational modeling of the peptide using Rosetta. Isotropic chemical shift data of isotopically labeled ghrelin provide information about the peptide's secondary structure. Spin diffusion experiments indicate that ghrelin binds to membranes via its lipidated Ser3. Further, Phe4, as well as electrostatics involving the peptide's positively charged residues and lipid polar headgroups, contribute to the binding energy. Other than the lipid anchor, ghrelin is highly flexible and mobile at the membrane surface. This observation is supported by our predicted model ensemble, which is in good agreement with experimentally determined chemical shifts. In the final ensemble of models, residues 8-17 form an α-helix, while residues 21-23 and 26-27 often adopt a polyproline II helical conformation. These helices appear to assist the peptide in forming an amphipathic conformation so that it can bind to the membrane. |
Databáze: | OpenAIRE |
Externí odkaz: |