Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome
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....
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2019-11-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/49138 |
| _version_ | 1811202764348325888 |
|---|---|
| author | Amanda B Abildgaard Amelie Stein Sofie V Nielsen Katrine Schultz-Knudsen Elena Papaleo Amruta Shrikhande Eva R Hoffmann Inge Bernstein Anne-Marie Gerdes Masanobu Takahashi Chikashi Ishioka Kresten Lindorff-Larsen Rasmus Hartmann-Petersen |
| author_facet | Amanda B Abildgaard Amelie Stein Sofie V Nielsen Katrine Schultz-Knudsen Elena Papaleo Amruta Shrikhande Eva R Hoffmann Inge Bernstein Anne-Marie Gerdes Masanobu Takahashi Chikashi Ishioka Kresten Lindorff-Larsen Rasmus Hartmann-Petersen |
| author_sort | Amanda B Abildgaard |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:44:10Z |
| format | Article |
| id | doaj.art-43692d501787457ab9d4d3b5d0673a78 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:44:10Z |
| publishDate | 2019-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-43692d501787457ab9d4d3b5d0673a782022-12-22T03:51:13ZengeLife Sciences Publications LtdeLife2050-084X2019-11-01810.7554/eLife.49138Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndromeAmanda B Abildgaard0Amelie Stein1https://orcid.org/0000-0002-5862-1681Sofie V Nielsen2Katrine Schultz-Knudsen3Elena Papaleo4https://orcid.org/0000-0002-7376-5894Amruta Shrikhande5Eva R Hoffmann6Inge Bernstein7Anne-Marie Gerdes8Masanobu Takahashi9Chikashi Ishioka10Kresten Lindorff-Larsen11https://orcid.org/0000-0002-4750-6039Rasmus Hartmann-Petersen12https://orcid.org/0000-0002-4155-7791Department of Biology, The Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, DenmarkDepartment of Biology, The Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, DenmarkDepartment of Biology, The Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, DenmarkDepartment of Biology, The Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, DenmarkDepartment of Biology, The Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, DenmarkDNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, DenmarkDNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, DenmarkDepartment of Surgical Gastroenterology, Aalborg University Hospital, Aalborg, DenmarkDepartment of Clinical Genetics, Rigshospitalet, Copenhagen, DenmarkDepartment of Medical Oncology, Tohoku University Hospital, Tohoku University, Sendai, JapanDepartment of Medical Oncology, Tohoku University Hospital, Tohoku University, Sendai, JapanDepartment of Biology, The Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, DenmarkDepartment of Biology, The Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, DenmarkDefective 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.https://elifesciences.org/articles/49138protein misfoldingprotein quality controlproteasomechaperone |
| spellingShingle | Amanda B Abildgaard Amelie Stein Sofie V Nielsen Katrine Schultz-Knudsen Elena Papaleo Amruta Shrikhande Eva R Hoffmann Inge Bernstein Anne-Marie Gerdes Masanobu Takahashi Chikashi Ishioka Kresten Lindorff-Larsen Rasmus Hartmann-Petersen Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome eLife protein misfolding protein quality control proteasome chaperone |
| title | Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome |
| title_full | Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome |
| title_fullStr | Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome |
| title_full_unstemmed | Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome |
| title_short | Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome |
| title_sort | computational and cellular studies reveal structural destabilization and degradation of mlh1 variants in lynch syndrome |
| topic | protein misfolding protein quality control proteasome chaperone |
| url | https://elifesciences.org/articles/49138 |
| work_keys_str_mv | AT amandababildgaard computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT ameliestein computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT sofievnielsen computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT katrineschultzknudsen computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT elenapapaleo computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT amrutashrikhande computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT evarhoffmann computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT ingebernstein computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT annemariegerdes computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT masanobutakahashi computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT chikashiishioka computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT krestenlindorfflarsen computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome AT rasmushartmannpetersen computationalandcellularstudiesrevealstructuraldestabilizationanddegradationofmlh1variantsinlynchsyndrome |