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

Ji Hye Yun, Minsup Kim, Kuglae Kim, Dongju Lee, Youngjin Jung, Daeseok Oh, Yoon Joo Ko, Art E. Cho, Hyun Soo Cho, Weontae Lee

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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 Asp902.50 plays a key role in allosteric sodium ion binding. Our data suggest that the sodium ion interaction of Asp902.50 in the allosteric pocket of MC4R is essential to its function, explaining the loss of function of the MC4RD90N mutant.

Original languageEnglish
Article number81835
Pages (from-to)1294-1302
Number of pages9
JournalBiochimica et Biophysica Acta - Biomembranes
Issue number6
Publication statusPublished - 2015 Jun


All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Cell Biology

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