PMC:4528928 / 12237-15023
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4528928","sourcedb":"PMC","sourceid":"4528928","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4528928","text":"3.2. Structural basis for the pathogenicity of MLH1 mutations \nStructural and functional information may be utilized to determine the pathogenicity of MLH1 mutations identified during genetic testing for hereditary cancer syndromes. Here, we present two such pathogenic variants, c.83C\u003eT (p.Pro28Leu) and c.464T\u003eG (p.Leu155Arg) (Thompson et al., 2014 ▸). Pro28 is a buried residue at the N-terminus of αA in the ATPase domain and is completely inaccessible to the solvent (Krissinel \u0026 Henrick, 2007 ▸). The introduction of a Leu at this tightly packed position in p.Pro28Leu is likely to introduce severe steric clashes, given its more extended side chain. Sterically, the most favorable rotamer still shows increased van der Waals (vdW) strain and steric clashes involving Gly54, Gly55, Ile59 and Ile176 that are likely to disrupt the core fold of the protein (Fig. 2 ▸ a).\nLeu155 is also buried in the α/β sandwich of the ATPase domain, between helix αB and the extended β-sheet (Fig. 2 ▸ b). Substitution by Arg at this position could have two consequences. Firstly, outside an active site or stabilizing secondary-structure element, the introduction of an unbalanced, buried charge is often considered to be destabilizing to protein structure (Kajander et al., 2000 ▸; Waldburger et al., 1995 ▸; Wimley et al., 1996 ▸). Incorporating the most favorable rotamer, the modeled Arg at position 155 is surrounded by a cluster of nonpolar residues (Ala31, Ile25, Ile107 and Val152) and is unable to form hydrogen bonds to nearby side-chain or main-chain atoms. The second structural consequence of p.Leu155Arg relates to the compact space in the center of the α/β sandwich, which imposes a steric constraint on the type of amino acid that can be accommodated at position 155. Compared with Leu, the more extended alkyl-guanidinium side chain of Arg introduces severe steric clashes, which disrupt the architecture of the elements (for example helix αD) that form the active site of the enzyme.\nGiven this structural rationale, we expect the MLH1 structure reported here to be of great clinical utility in the analysis of missense variants found in patients recommended for genetic testing. The structure provides a robust platform, in combination with other strong functional or clinical evidence, to help to determine the clinical effect of loss-of-function mutations. We caution, however, against reliance on this model to predict a benign effect in a clinical setting, as truly pathogenic variants may fall within the ‘normal’ functional range. Therefore, other factors must be considered when a seemingly benign substitution is encountered, including the possibility that a nonsynonymous change may have an effect on mRNA splicing or post-translational modification of the protein.","divisions":[{"label":"Title","span":{"begin":6,"end":65}}],"tracks":[]}