In silico mutagenesis: a case study of the melanocortin 4 receptor.
FASEB J
; 23(9): 3059-69, 2009 Sep.
Article
en En
| MEDLINE
| ID: mdl-19417090
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Simulación por Computador
/
Mutagénesis
/
Receptor de Melanocortina Tipo 4
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
FASEB J
Asunto de la revista:
BIOLOGIA
/
FISIOLOGIA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos