Computational analysis of missense mutations causing Snyder-Robinson syndrome.
The Snyder-Robinson syndrome is caused by missense mutations in the spermine sythase gene that encodes a protein (SMS) of 529 amino acids. Here we investigate, in silico, the molecular effect of three missense mutations, c.267G>A (p.G56S), c.496T>G (p.V132G), and c.550T>C (p.I150T) in SMS that were clinically identified to cause the disease. Single-point energy calculations, molecular dynamics simulations, and pKa calculations revealed the effects of these mutations on SMS's stability, flexibility, and interactions. It was predicted that the catalytic residue, Asp276, should be protonated prior binding the substrates. The pKa calculations indicated the p.I150T mutation causes pKa changes with respect to the wild-type SMS, which involve titratable residues interacting with the S-methyl-5'-thioadenosine (MTA) substrate. The p.I150T missense mutation was also found to decrease the stability of the C-terminal domain and to induce structural changes in the vicinity of the MTA binding site. The other two missense mutations, p.G56S and p.V132G, are away from active site and do not perturb its wild-type properties, but affect the stability of both the monomers and the dimer. Specifically, the p.G56S mutation is predicted to greatly reduce the affinity of monomers to form a dimer, and therefore should have a dramatic effect on SMS function because dimerization is essential for SMS activity.
Zhang
Zhe
Z
Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina 29634, USA.
Teng
Shaolei
S
Wang
Liangjiang
L
Schwartz
Charles E
CE
Alexov
Emil
E
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D006801:Humans; D020407:Internet; D038901:X-Linked Intellectual Disability / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics*; D055503:Protein Multimerization; D013097:Spermine Synthase / Q000737:chemistry / Q000235:genetics; D013816:Thermodynamics; D013872:Thionucleosides / Q000378:metabolism
D013872:Thionucleosides; C063476:5'-thioadenosine; D013097:Spermine Synthase; D000241:Adenosine