TY - JOUR TI - Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome AU - Abildgaard, Amanda B AU - Stein, Amelie AU - Nielsen, Sofie V AU - Schultz-Knudsen, Katrine AU - Papaleo, Elena AU - Shrikhande, Amruta AU - Hoffmann, Eva R AU - Bernstein, Inge AU - Gerdes, Anne-Marie AU - Takahashi, Masanobu AU - Ishioka, Chikashi AU - Lindorff-Larsen, Kresten AU - Hartmann-Petersen, Rasmus A2 - Fleishman, Sarel Jacob A2 - Kuriyan, John A2 - Fleishman, Sarel Jacob VL - 8 PY - 2019 DA - 2019/11/07 SP - e49138 C1 - eLife 2019;8:e49138 DO - 10.7554/eLife.49138 UR - https://doi.org/10.7554/eLife.49138 AB - Defective mismatch repair leads to increased mutation rates, and germline loss-of-function variants in the repair component MLH1 cause the hereditary cancer predisposition disorder known as Lynch syndrome. Early diagnosis is important, but complicated by many variants being of unknown significance. Here we show that a majority of the disease-linked MLH1 variants we studied are present at reduced cellular levels. We show that destabilized MLH1 variants are targeted for chaperone-assisted proteasomal degradation, resulting also in degradation of co-factors PMS1 and PMS2. In silico saturation mutagenesis and computational predictions of thermodynamic stability of MLH1 missense variants revealed a correlation between structural destabilization, reduced steady-state levels and loss-of-function. Thus, we suggest that loss of stability and cellular degradation is an important mechanism underlying many MLH1 variants in Lynch syndrome. Combined with analyses of conservation, the thermodynamic stability predictions separate disease-linked from benign MLH1 variants, and therefore hold potential for Lynch syndrome diagnostics. KW - protein misfolding KW - protein quality control KW - proteasome KW - chaperone JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -