Analyzing effects of naturally occurring missense mutations

Abstract

Single-point mutation in genome, for example, single-nucleotide polymorphism (SNP) or rare genetic mutation, is the change of a single nucleotide for another in the genome sequence. Some of them will produce an amino acid substitution in the corresponding protein sequence (missense mutations); others will not. This paper focuses on genetic mutations resulting in a change in the amino acid sequence of the corresponding protein and how to assess their effects on protein wild-type characteristics. The existing methods and approaches for predicting the effects of mutation on protein stability, structure, and dynamics are outlined and discussed with respect to their underlying principles. Available resources, either as stand-alone applications or webservers, are pointed out as well. It is emphasized that understanding the molecular mechanisms behind these effects due to these missense mutations is of critical importance for detecting disease-causing mutations. The paper provides several examples of the application of 3D structure-based methods to model the effects of protein stability and protein-protein interactions caused by missense mutations as well.

Figure 1

(a) The structural and flexibility differences between the simulated WT and mutant structures. The black line represents the RMSF of the WT structure and the red line represents the mutant protein. (b) 3D structure of the C2 domain of the WT FV. The S–S bond is marked in yellow and the loop 2042–2053 is indicated by the arrow.

Figure 2

3D structure of human SMS with three missense mutation sites. Two subunits were represented by ribbon in cyan and magenta. Three mutation sites were shown with sphere representation: G56S in orange, V132G in white and I150T in green. The substrates of SPD and MTA were shown in red sticks and blue sticks, respectively.

Figure 3

Effects on dimerization. (a) G56S: we superimposed WT structure (presented with two chains in white) and mutant structure (presented with Only one chain in green). Cyan stick represented Gly in the WT structure and magenta stick represented Ser in the mutant structure; (b) V132G: Only the region around the mutation site was shown in the figure. We superimpose the WT structure (presented with two chains in white) and mutant (presented with only one chain in green). The orange stick represented Val in the WT structure and red stick represented Gly in the mutant structure.

Figure 4

Effects on monomer stability. (a) G56S: N-terminal domain of both WT monomer (white) and mutant monomer (green) are superimposed. Cyan stick represented Gly in the WT structure and magenta represented Ser in the mutant structure; (b) V132G: C-terminal domain of both WT monomer (white) and mutant monomer (green) are superimposed. We use stick and ball representation in orange to represent Val in the WT structure and in red to represent Gly in the mutant structure.