A Glance into MTHFR Deficiency at a Molecular Level
| Autor: | Castrense Savojardo, Giulia Babbi, Davide Baldazzi, Pier Luigi Martelli, Rita Casadio |
|---|---|
| Přispěvatelé: | Savojardo C., Babbi G., Baldazzi D., Martelli P.L., Casadio R. |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
solvent accessibility
MTHFR deficiency MTHFR variants functional annotation structural annotation disease related variations ΔΔG predictions consensus method protein-protein interactions disease HMM models QH301-705.5 MTHFR variant Catalysis Article Inorganic Chemistry Disease HMM model Catalytic Domain Humans Protein Interaction Maps Physical and Theoretical Chemistry Biology (General) ΔΔG prediction Molecular Biology QD1-999 Spectroscopy Methylenetetrahydrofolate Reductase (NADPH2) Organic Chemistry General Medicine Computer Science Applications Chemistry Psychotic Disorders Muscle Spasticity Disease related variation Protein‐protein interaction Homocystinuria Protein Interaction Map Human |
| Zdroj: | International Journal of Molecular Sciences, Vol 23, Iss 167, p 167 (2022) International Journal of Molecular Sciences; Volume 23; Issue 1; Pages: 167 International Journal of Molecular Sciences |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | MTHFR deficiency still deserves an investigation to associate the phenotype to protein structure variations. To this aim, considering the MTHFR wild type protein structure, with a catalytic and a regulatory domain and taking advantage of state-of-the-art computational tools, we explore the properties of 72 missense variations known to be disease associated. By computing the thermodynamic ΔΔG change according to a consensus method that we recently introduced, we find that 61% of the disease-related variations destabilize the protein, are present both in the catalytic and regulatory domain and correspond to known biochemical deficiencies. The propensity of solvent accessible residues to be involved in protein-protein interaction sites indicates that most of the interacting residues are located in the regulatory domain, and that only three of them, located at the interface of the functional protein homodimer, are both disease-related and destabilizing. Finally, we compute the protein architecture with Hidden Markov Models, one from Pfam for the catalytic domain and the second computed in house for the regulatory domain. We show that patterns of disease-associated, physicochemical variation types, both in the catalytic and regulatory domains, are unique for the MTHFR deficiency when mapped into the protein architecture. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|