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

Wu H, Zeng H, Lam R, Tempel W, Kerr ID, Min J - Acta Crystallogr F Struct Biol Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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fig2: 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.

Mentions: Structural 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>T (p.Pro28Leu) and c.464T>G (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 & 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).


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

Wu H, Zeng H, Lam R, Tempel W, Kerr ID, Min J - Acta Crystallogr F Struct Biol Commun (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528928&req=5

fig2: 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.
Mentions: Structural 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>T (p.Pro28Leu) and c.464T>G (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 & 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).

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.

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.

No MeSH data available.


Related in: MedlinePlus