Structural and Dynamic Disturbances Revealed by Molecular Dynamics Simulations Predict the Impact on Function of CCT5 Chaperonin Mutations Associated with Rare Severe Distal Neuropathies.
Federica Scalia, Giosuè Lo Bosco, Letizia Paladino, Alessandra Maria Vitale, Leila Noori, Everly Conway de Macario, Alberto J L Macario, Fabio Bucchieri, Francesco Cappello, Fabrizio Lo Celso
Author Information
Federica Scalia: Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy.
Giosuè Lo Bosco: Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy.
Letizia Paladino: Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy. ORCID
Alessandra Maria Vitale: Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy. ORCID
Leila Noori: Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy.
Everly Conway de Macario: Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy.
Alberto J L Macario: Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy. ORCID
Fabio Bucchieri: Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy.
Francesco Cappello: Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy. ORCID
Fabrizio Lo Celso: Department of Physics and Chemistry-Emilio Segrè, University of Palermo, 90128 Palermo, Italy. ORCID
Mutations in genes encoding molecular chaperones, for instance the genes encoding the subunits of the chaperonin CCT (chaperonin containing TCP-1, also known as TRiC), are associated with rare neurodegenerative disorders. Using a classical molecular dynamics approach, we investigated the occurrence of conformational changes and differences in physicochemical properties of the CCT5 mutations His147Arg and Leu224Val associated with a sensory and a motor distal neuropathy, respectively. The apical domain of both variants was substantially but differently affected by the mutations, although these were in other domains. The distribution of hydrogen bonds and electrostatic potentials on the surface of the mutant subunits differed from the wild-type molecule. Structural and dynamic analyses, together with our previous experimental data, suggest that genetic mutations may cause different changes in the protein-binding capacity of CCT5 variants, presumably within both hetero- and/or homo-oligomeric complexes. Further investigations are necessary to elucidate the molecular pathogenic pathways of the two variants that produce the two distinct phenotypes. The data and clinical observations by us and others indicate that CCT chaperonopathies are more frequent than currently believed and should be investigated in patients with neuropathies.
