Solution structure of the transmembrane 2 domain of the human melanocortin-4 receptor in sodium dodecyl sulfate (SDS) micelles and the functional implication of the D90N mutant

Biochimica Et Biophysica Acta
Ji-Hye YunWeontae Lee

Abstract

The melanocortin receptors (MCRs) are members of the G protein-coupled receptor (GPCR) 1 superfamily with seven transmembrane (TM) domains. Among them, the melanocortin-4 receptor (MC4R) subtype has been highlighted recently by genetic studies in obese humans. In particular, in a patient with severe early-onset obesity, a novel heterozygous mutation in the MC4R gene was found in an exchange of Asp to Asn in the 90th amino acid residue located in the TM 2 domain (MC4RD90N). Mutations in the MC4R gene are the most frequent monogenic causes of severe obesity and are described as heterozygous with loss of function. We determine solution structures of the TM 2 domain of MC4R (MC4RTM2) and compared secondary structure of Asp90 mutant (MC4RTM2-D90N) in a micelle environment by nuclear magnetic resonance (NMR) spectroscopy. NMR structure shows that MC4RTM2 forms a long α-helix with a kink at Gly98. Interestingly, the structure of MC4RTM2-D90N is similar to that of MC4RTM2 based on data from CD and NMR spectrum. However, the thermal stability and homogeneity of MC4RD90N is quite different from those of MC4R. The structure from molecular modeling suggests that Asp90(2.50) plays a key role in allosteric sodium ion binding. Our data sugges...Continue Reading

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Citations

Mar 25, 2016·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Aditya PandeyJan K Rainey
Apr 26, 2016·Chemical Reviews·Stephen Boulton, Giuseppe Melacini
Jun 19, 2018·Frontiers in Pharmacology·Noureldin SalehPatrick Scheerer
Oct 21, 2020·International Journal of Molecular Sciences·Li-Kun Yang, Ya-Xiong Tao

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