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dc.contributor.author
Guérin, Diego Marcelo Alejandro
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dc.contributor.author
Digilio, Ayelen
dc.contributor.author
Branda, Maria Marta
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dc.date.available
2022-10-18T12:12:10Z
dc.date.issued
2021-12
dc.identifier.citation
Guérin, Diego Marcelo Alejandro; Digilio, Ayelen; Branda, Maria Marta; Dimeric Rhodopsin R135L Mutant-Transducin-like Complex Sheds Light on Retinitis Pigmentosa Misfunctions; American Chemical Society; Journal of Physical Chemistry B; 125; 47; 12-2021; 12958-12971
dc.identifier.issn
1520-6106
dc.identifier.uri
http://hdl.handle.net/11336/173723
dc.description.abstract
Rhodopsin (RHO) is a light-sensitive pigment in the retina and the main prototypical protein of the G-protein-coupled receptor (GCPR) family. After receiving a light stimulus, RHO and its cofactor retinylidene undergo a series of structural changes that initiate an intricate transduction mechanism. Along with RHO, other partner proteins play key roles in the signaling pathway. These include transducin, a GTPase, kinases that phosphorylate RHO, and arrestin (Arr), which ultimately stops the signaling process and promotes RHO regeneration. A large number of RHO genetic mutations may lead to very severe retinal dysfunction and eventually to impaired dark adaptation disease called autosomal dominant retinitis pigmentosa (adRP). In this study, we used molecular dynamics (MD) simulations to evaluate the different behaviors of the dimeric form of wild-type RHO (WT dRHO) and its mutant at position 135 of arginine to leucine (dR135L), both in the free (noncomplexed) and in complex with the transducin-like protein (Gtl). Gtl is a heterotrimeric model composed of a mixture of human and bovine G proteins. Our calculations allow us to explain how the mutation causes structural changes in the RHO dimer and how this can affect the signal that transducin generates when it is bound to RHO. Moreover, the structural modifications induced by the R135L mutation can also account for other misfunctions observed in the up- and downstream signaling pathways. The mechanism of these dysfunctions, together with the transducin activity reduction, provides structure-based explanations of the impairment of some key processes that lead to adRP.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Chemical Society
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dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
G PROTEIN-COUPLED RECEPTORS
dc.subject
RHODOPSIN MUTANT
dc.subject
RETINITIS PIGMENTOSA
dc.subject
MOLECULAR DYNAMIC SIMULATIONS
dc.subject.classification
Otras Ciencias Físicas
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dc.subject.classification
Ciencias Físicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Dimeric Rhodopsin R135L Mutant-Transducin-like Complex Sheds Light on Retinitis Pigmentosa Misfunctions
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2022-09-20T15:45:02Z
dc.journal.volume
125
dc.journal.number
47
dc.journal.pagination
12958-12971
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Washington
dc.description.fil
Fil: Guérin, Diego Marcelo Alejandro. Universidad del País Vasco; España
dc.description.fil
Fil: Digilio, Ayelen. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Departamento de Física; Argentina
dc.description.fil
Fil: Branda, Maria Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich". Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich"; Argentina
dc.journal.title
Journal of Physical Chemistry B
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1021/acs.jpcb.1c06348
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acs.jpcb.1c06348
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