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, Weon Tae Lee

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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
Volume1848
Issue number6
DOIs
Publication statusPublished - 2015 Jan 1

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Receptor, Melanocortin, Type 4
Micelles
Sodium Dodecyl Sulfate
Magnetic Resonance Spectroscopy
Genes
Sodium
Melanocortin Receptors
Nuclear magnetic resonance
Ions
Mutation
Molecular modeling
Morbid Obesity
G-Protein-Coupled Receptors
Molecular Structure
Nuclear magnetic resonance spectroscopy
human MC4R protein
Thermodynamic stability
Obesity
Hot Temperature
Amino Acids

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Cell Biology

Cite this

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title = "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",
abstract = "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.",
author = "Yun, {Ji Hye} and Minsup Kim and Kuglae Kim and Dongju Lee and Youngjin Jung and Daeseok Oh and Ko, {Yoon Joo} and Cho, {Art E.} and Cho, {Hyun Soo} and Lee, {Weon Tae}",
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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. / Yun, Ji Hye; Kim, Minsup; Kim, Kuglae; Lee, Dongju; Jung, Youngjin; Oh, Daeseok; Ko, Yoon Joo; Cho, Art E.; Cho, Hyun Soo; Lee, Weon Tae.

In: Biochimica et Biophysica Acta - Biomembranes, Vol. 1848, No. 6, 81835, 01.01.2015, p. 1294-1302.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Yun, Ji Hye

AU - Kim, Minsup

AU - Kim, Kuglae

AU - Lee, Dongju

AU - Jung, Youngjin

AU - Oh, Daeseok

AU - Ko, Yoon Joo

AU - Cho, Art E.

AU - Cho, Hyun Soo

AU - Lee, Weon Tae

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

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