Computational analysis of missense mutations causing Snyder-Robinson syndrome

Abstract

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.267G4A (p.G56S), c.496T4G (p.V132G), and c.550T4C (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 0 -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.

Structural and physico-chemical effects of disease and non-disease nsSNPs on proteins

“…In addition, it was demonstrated computationally that H-bonding and/or salt bridge disruptions are almost always disease-causing if they are in close proximity to the active site [21–23]. In many cases, the mutations were found to decrease the number of intramolecular H-bonds within a protein or the number of H-bonds that the protein makes with DNA or with the solvent [24, 25].…”

Protein-protein interaction sites are hot spots for disease-associated nonsynonymous SNPs

“…Consequently, several groups have analyzed the relationships between nsSNPs and their location in a folded protein (e.g., [Burke et al, 2007;Wang and Moult, 2001;. However, proteins do not function in isolation and therefore it is vital to follow a systems biology approach and consider the effect of any nsSNP in terms of the mechanism by which the mutated protein interacts with others [Gong et al, 2011;Schuster-Bockler and Bateman, 2008;Teng et al, 2009;Zhang et al, 2010]. We now have experimental data on protein interactions both in terms of identifying the interacting partners (the interactome) and having 3D structures for complexes.…”

“…However, conformational rearrangement of the protein interface could alleviate some of these adverse structural changes. Modeling of the energetics of disease-causing nsSNPs at interfaces using energy calculations suggests that often there is very little difference in the free energy of association between the wild-type and the disease-causing variant due to conformational rearrangements [Teng et al, 2009] [Zhang et al, 2010]. Second, we examined common polymorphisms.…”

In silico analysis of mutations occurring in the protein N-acetylgalactosamine-6-sulfatase (GALNS) and causing mucopolysaccharidosis IVA

“…Tomatsu et al (2005) and Rivera-Colón et al (2012) showed that missense mutations [also called non synonymous substitution (Zhang et al, 2010(Zhang et al, , 2012] are the most common cause of MPS IVA. It causes amino acid changes due to single nucleotide polymorphisms, which can drastically change protein structure and function.…”