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Mutationally induced disulfide bond formation within the third extracellular loop causes melanocortin 4 receptor

Patrick Tarnow1, Torsten Schoneberg, Heiko Krude

  • 1Otto Heubner Centrum für Kinderheilkunde und Jugendmedizin, Pädiatrische Endokrinologie, Charité Campus Virchow-Klinikum, Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

The Journal of Biological Chemistry
|September 25, 2003
PubMed

Insights

A mutation in the melanocortin 4 receptor (MC4R) gene causes obesity by disrupting disulfide bonds. This study reveals a new mechanism of receptor malfunction involving abnormal disulfide bond formation.

Area of Science:

  • Genetics
  • Molecular Biology
  • Endocrinology

Background:

  • Severe early-onset obesity is often linked to genetic factors.
  • Mutations in the melanocortin 4 receptor (MC4R) gene are a known cause of obesity.
  • Understanding MC4R function is crucial for developing obesity treatments.

Purpose of the Study:

  • To identify and characterize mutations in the MC4R gene associated with severe early-onset obesity.
  • To elucidate the molecular mechanism by which identified mutations lead to receptor dysfunction.
  • To explore novel mechanisms of G-protein-coupled receptor (GPCR) malfunction.

Main Methods:

  • Screening of MC4R gene in patients with severe early-onset obesity.
  • Functional characterization of identified MC4R mutations using in vitro assays.
  • Analysis of disulfide bond formation and its impact on receptor activity and cell surface expression.
  • Site-directed mutagenesis to disrupt specific disulfide bonds.

Main Results:

  • A homozygous missense mutation (C271R) was identified in two siblings with obesity.
  • The C271R mutation resulted in reduced MC4R affinity for agonists and decreased cell surface expression.
  • Evidence suggests the C271R mutation induces receptor malfunction via an aberrant disulfide bond between Cys-277 and Cys-279.
  • Disruption of this aberrant disulfide bond restored normal MC4R potency.

Conclusions:

  • The C271R mutation in MC4R causes obesity through a novel mechanism involving the formation of a detrimental disulfide bond.
  • This study reveals a new way cysteine residues can contribute to GPCR malfunction.
  • Targeting aberrant disulfide bond formation may offer therapeutic strategies for obesity and other related disorders.

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