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In silico mutagenesis: a case study of the melanocortin 4 receptor

Yana Bromberg^*,,1, John Overton, Christian Vaisse^||, Rudolph L. Leibel^,2 and Burkhard Rost^*,,,2

^* Department of Biochemistry and Molecular Biophysics,

Columbia University Center for Computational Biology and Bioinformatics,

Division of Molecular Genetics, Naomi Berrie Diabetes Center, and

Northeast Structural Genomics Consortium and New York Consortium on Membrane Protein Structure, Columbia University, New York, New York, USA; and

^|| Diabetes Center and Department of Medicine, University of California, San Francisco, California, USA

¹ Correspondence: Columbia University Center for Computational Biology and Bioinformatics, 1130 St. Nicholas Ave, Room 802, New York, NY 10032, USA. E-mail: bromberg{at}rostlab.org

The melanocortin 4 receptor (MC4R) is a G-protein-coupled receptor (GPCR) and a key molecule in the regulation of energy homeostasis. At least 159 substitutions in the coding region of human MC4R (hMC4R) have been described experimentally; over 80 of those occur naturally, and many have been implicated in obesity. However, assessment of the presumably functionally essential residues remains incomplete. Here we have performed a complete in silico mutagenesis analysis to assess the functional essentiality of all possible nonnative point mutants in the entire hMC4R protein (332 residues). We applied SNAP, which is a method for quantifying functional consequences of single amino acid (AA) substitutions, to calculate the effects of all possible substitutions at each position in the hMC4R AA sequence. We compiled a mutability score that reflects the degree to which a particular residue is likely to be functionally important. We performed the same experiment for a paralogue human melanocortin receptor (hMC1R) and a mouse orthologue (mMC4R) in order to compare computational evaluations of highly related sequences. Three results are most salient: 1) our predictions largely agree with the available experimental annotations; 2) this analysis identified several AAs that are likely to be functionally critical, but have not yet been studied experimentally; and 3) the differential analysis of the receptors implicates a number of residues as specifically important to MC4Rs vs. other GPCRs, such as hMC1R.—Bromberg, Y., Overton, J., Vaisse, C., Leibel, R. L., Rost, B. In silico mutagenesis: a case study of the melanocortin 4 receptor.

Key Words: MC4R • MC1R • SNAP • active functional site • obesity • diabetes

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