Effects of pathological mutations on the stability of a conserved amino acid triad in retinoschisin.
A three-dimensional model has been calculated for the discoidin domain of retinoschisin (RS1), the protein involved in the X-linked juvenile retinoschisis. The model allows for a mapping of the pathological retinoschisis missense mutations and a rationale for the structural effects of an evolutionary conserved surface exposed triad (W122-R200-W163). Molecular dynamics simulations of the triad mutants models, together with ab initio energy calculations of the complexes corresponding to the triad show that the observed pathological mutations sensibly destabilize local interactions and the entire fold. Moreover the presented model reveals evidence of a putative site for membrane association.
Fraternali
Franca
F
National Institute for Medical Research, Department of Mathematical Biology, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Cavallo
Luigi
L
Musco
Giovanna
G
D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D005136:Eye Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012984:Software
D005136:Eye Proteins; C108726:RS1 protein, human