Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome

Abstract

Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson-Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot's syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants.

Keywords: ATPase; GHKL; Lynch syndrome; mismatch repair.

Figure 1

Superimposition of hLN40 and E. coli LN40 (PDB entry 1b62). hLN40 is colored yellow, while the E. coli homolog is colored green. The ATPase and transducer domains are located to the right and left, respectively, of the short loop colored blue. Residues in the ATP-binding loop of hLN40 are colored magenta, while those in E. coli LN40 are colored pink (the loop in the latter is ordered owing to extensive crystal contacts). In hLN40, ADP is depicted in stick representation and Mg²⁺ is shown as a green sphere. Secondary-structure elements are labelled beginning at the N-­terminus, with the first helix being αA and the first β-strand being β1.

Figure 2

Structural basis for the pathogenicity of MLH1 missense variants. Ribbon diagrams showing the structural consequences of (a) c.83C>T (p.Pro28Leu) and (b) c.464T>G (p.Leu155Arg). The figure is colored as in Fig. 1 ▸, with the exception that structural elements outside the core Bergerat fold are colored cyan. Important amino acids around the mutation are represented as sticks. The mutation is colored grey. Red circles represent steric clashes with surrounding parts of the structure. For clarity, the transducer domain is omitted from both figures.