Molecular mechanisms of disease-causing missense mutations

Abstract

Genetic variations resulting in a change of amino acid sequence can have a dramatic effect on stability, hydrogen bond network, conformational dynamics, activity and many other physiologically important properties of proteins. The substitutions of only one residue in a protein sequence, so-called missense mutations, can be related to many pathological conditions and may influence susceptibility to disease and drug treatment. The plausible effects of missense mutations range from affecting the macromolecular stability to perturbing macromolecular interactions and cellular localization. Here we review the individual cases and genome-wide studies that illustrate the association between missense mutations and diseases. In addition, we emphasize that the molecular mechanisms of effects of mutations should be revealed in order to understand the disease origin. Finally, we report the current state-of-the-art methodologies that predict the effects of mutations on protein stability, the hydrogen bond network, pH dependence, conformational dynamics and protein function.

Keywords: 3D; HDL; MD; RTK; SNP; SVM; diseases; genetic variation; high-density lipoprotein; molecular dynamics; rare mutations; receptor tyrosine kinase; single nucleotide polymorphism; support vector machine; three-dimensional.

Figure 1

The change in the folding free energy (ΔΔG) may be evaluated using two different methods: (1) using the difference in the folding free energy values calculated from the transition from an unfolded to a folded state of the wild type (ΔG^WT(folding)) minus the mutant type (ΔG^MT(folding)) shown with black arrows; or (2) using the difference in the folding free energy between the folded state of the wild type and mutant type (ΔG^folded(WT-MT)) minus the folding free energy between the unfolded state of the wild type and mutant type (ΔG^unfolded(WT-MT)) shown with red arrows.

Figure 2

The region at the mutation site N550 of the wild type 3D structure of Isoform 3 Lactosylceramide alpha-2,3-sialyltransferase and mutant model which was built using 2wmlA.pdb as a template: (a) the wild type with N550 in the left panel and (b) the mutant N550K in the right panel, both centered at the mutation site. The hydrogen bonds between N550 and its neighbors in the wild type are shown with dashed black lines.