A small chaperone improves folding and routing of rhodopsin mutants linked to inherited blindness
Il 12/02/2018 ore 14.30 - 15.30
Sala conferenze Cnr, Area della ricerca Na1, Via P. Castellino, 111 - 80131 Napoli
Francesca Fanelli from the Department of Life Sciences, University of Modena and Reggio Emilia, will give a seminar on Retinitis Pigmentosa (RP). It comprises a group of hereditary human diseases that are the most common cause of inherited blindness in developed countries. The autosomal dominant form of RP (adRP) is largely linked to misfolding mutations of the RHO gene encoding for the G protein coupled receptor rhodopsin.
Molecular simulations coupled to the graph-based Protein Structure Network (PSN) analysis and in vitro experiments served to determine the effects of 33 different adRP rhodopsin mutations on the native network of intramolecular interactions funding the native state and on the subcellular localization of the protein in the presence and absence of the retinal ligand.
The integration between atomic and subcellular levels of analysis was accomplished by the linear correlation between indices of mutational impairment in structure network and in trafficking. The graph-based index of structural perturbation served also to divide the mutants in four clusters, consistent with their differences in subcellular localization and responsiveness to retinal.
The putative stability core of the protein inferred from the PSN analysis was targeted by virtual screening of over 300000 anionic compounds. A selection of 20 hits was in vitro assayed leading to the discovery of a pharmacological chaperone more powerful than retinal on three adRP mutants selected from the most responsive clusters. The ability of the novel chaperone to relieve perturbation in the native structure network is consistent with its ability to correct misrouting of the mutated protein.
Via P. Castellino, 111 80131 Napoli
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