Journal article
Assessing the predicted impact of single amino acid substitutions in MAPK proteins for CAGI6 challenges
Human genetics, Vol.144(2-3), pp.265-280
02/2025
PMID: 39976676
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Source: InCites
Abstract
New thermodynamic and functional studies have been recently conducted to evaluate the impact of amino acid substitutions on the Mitogen Activated Protein Kinases 1 and 3 (MAPK1/3). The Critical Assessment of Genome Interpretation (CAGI) data provider, at Sapienza University of Rome, measured the unfolding free energy and the enzymatic activity of a set of variants (MAPK challenge dataset). Thermodynamic measurements for the denaturant-induced equilibrium unfolding of the phosphorylated and unphosphorylated forms of the MAPKs were obtained by monitoring the far-UV circular dichroism and intrinsic fluorescence changes as a function of denaturant concentration. These values have been used to calculate the change in unfolding free energy between the variant and wild-type proteins at zero concentration of denaturant (ΔΔGH<sub>2</sub> O). The enzymatic activity of the phosphorylated MAPKs variants was also measured using Chelation-Enhanced Fluorescence to monitor the phosphorylation of a peptide substrate. The MAPK challenge dataset, composed of a total of 23 single amino acid substitutions (11 and 12 for MAPK1 and MAPK3, respectively), was used to assess the effectiveness of the computational methods in predicting the ΔΔGH<sub>2</sub> O values, associated with the variants, and categorize them as destabilizing and not destabilizing. The data on the enzymatic activity of the MAPKs mutants were used to assess the performance of the methods for predicting the functional impact of the variants. For the sixth edition of CAGI, thirteen independent research groups from four continents (Asia, Australia, Europe and North America) submitted > 80 sets of predictions, obtained from different approaches. In this manuscript, we summarized the results of our assessment to highlight the possible limitations of the available algorithms.
Details
- Title
- Assessing the predicted impact of single amino acid substitutions in MAPK proteins for CAGI6 challenges
- Creators
- Paola Turina - University of BolognaMaria Petrosino - SURCarlos A Enriquez Sandoval - University of BolognaLeonore Novak - SURAlessandra Pasquo - ENEA CR Frascati (Italy)Emil Alexov - Clemson UniversityMuttaqi Ahmad Alladin - Indian Institute of Science BangaloreDavid B. Ascher - The University of QueenslandGiulia Babbi - University of BolognaConstantina Bakolitsa - University of California, BerkeleyRita Casadio - University of BolognaJianlin Cheng - University of MissouriPiero Fariselli - University of TurinLukas Folkman - Griffith UniversityAkash Kamandula - Northeastern UniversityPanagiotis Katsonis - Baylor College of MedicineMinghui Li - Soochow UniversityDong Li - Université Libre de BruxellesOlivier Lichtarge - Baylor College of MedicineSajid Mahmud - University of MissouriPier Luigi Martelli - University of BolognaDebnath Pal - Indian Institute of Science BangaloreShailesh Kumar Panday - Clemson UniversityDouglas E V Pires - The University of MelbourneStephanie Portelli - The University of QueenslandFabrizio Pucci - Université Libre de BruxellesCarlos H M Rodrigues - Baker Heart and Diabetes InstituteMarianne Rooman - Université Libre de BruxellesCastrense Savojardo - University of BolognaMartin Schwersensky - Université Libre de BruxellesYang Shen - Texas A&M UniversityAlexey V. Strokach - University of TorontoYuanfei Sun - Texas A&M UniversityJunwoo Woo - 3 Billion (South Korea)Predrag Radivojac - Northeastern UniversitySteven E. Brenner - University of California, BerkeleyRoberta Chiaraluce - SURValerio Consalvi - SUREmidio Capriotti - University of Bologna
- Publication Details
- Human genetics, Vol.144(2-3), pp.265-280
- Publisher
- Springer Nature; NEW YORK
- Grant note
- Ministero dell'Istruzione, dell'Universit e della Ricerca
We acknowledge all the CAGI organizers for their support in the organization of the MAPK Challenges.
- Identifiers
- 991013345939602368
- Copyright
- © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025.
- Academic Unit
- Faculty of Science and Engineering
- Language
- English
- Resource Type
- Journal article