A Small Chaperone Improves Folding and Routing of Rhodopsin Mutants Linked to Inherited Blindness
Petra Behnen,
Angelo Felline,
Antonella Comitato,
Maria Teresa Di Salvo,
Francesco Raimondi,
Sahil Gulati,
Shirin Kahremany,
Krzysztof Palczewski,
Valeria Marigo,
Francesca Fanelli
Affiliations
Petra Behnen
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy
Angelo Felline
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy
Antonella Comitato
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy
Maria Teresa Di Salvo
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy
Francesco Raimondi
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy
Sahil Gulati
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, 1819 East 101st Street, Cleveland, OH 44106, USA
Shirin Kahremany
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Krzysztof Palczewski
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, 1819 East 101st Street, Cleveland, OH 44106, USA
Valeria Marigo
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy; Center for Neuroscience and Neurotechnology, via Campi 287, 41125 Modena, Italy; Corresponding author
Francesca Fanelli
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy; Center for Neuroscience and Neurotechnology, via Campi 287, 41125 Modena, Italy; Corresponding author
Summary: The autosomal dominant form of retinitis pigmentosa (adRP) is a blindness-causing conformational disease largely linked to mutations of rhodopsin. Molecular simulations coupled to the graph-based protein structure network (PSN) analysis and in vitro experiments were conducted to determine the effects of 33 adRP rhodopsin mutations on the structure and routing of the opsin protein. The integration of atomic and subcellular levels of analysis was accomplished by the linear correlation between indices of mutational impairment in structure network and in routing. The graph-based index of structural perturbation served also to divide the mutants in four clusters, consistent with their differences in subcellular localization and responses to 9-cis retinal. The stability core of opsin inferred from PSN analysis was targeted by virtual screening of over 300,000 anionic compounds leading to the discovery of a reversible orthosteric inhibitor of retinal binding more effective than retinal in improving routing of three adRP mutants. : Structural Biology; Protein Structure Aspects; Biophysics; Protein Folding Subject Areas: Structural Biology, Protein Structure Aspects, Biophysics, Protein Folding
