Dynamic modelling of the complex transducin-rhodopsin R135L mutant explains major dysfunctions present in Retinitis Pigmentosa (night blindness)

A. DIGILIO; A. GIORGETTI; M.M. BRANDA; F. FERREIRA; D.M.A. GUÉRIN; E. PEPE WEIGEL; P. CARLONI

Jornada; Primeras jornadas virtuales de la Sociedad Argentina de Biofísica; 2020

Rhodopsin(RHO) is the complex between opsin, a 7-helix bundle membrane protein, and its cofactor retinylidene (RET). RHO is foundin the retina of vertebrates and is considered a prototypical member of theG-protein-coupled receptors (GCPRs) family. When RET absorbs a photon, both RETand opsin undergo a series of structural changes that lead RHO to its activestate (RHO*), and from this stage RHO triggers the light transduction mechanismin the eye.Uponactivation, RHO* can bind its partner protein transducin (Gi), a GTP-ase thatconverts free cytosolic GDP into GTP, and by this way activates second messengersinvolved in the down-stream signalling pathway. A large number of RHO geneticmutations may lead to retinal dysfunction and out of them the most severeimpair the eye adaptation to darkness or night blindness. This disease is also calledautosomal dominant Retinitis Pigmentosa (adRP), and the genetic mutation in RHO,Arg-135-Leu (R135L), is one of its causative. In this study we used MolecularDynamics (MD) to evaluate the structural differences between the dimeric formof native RHO and of R135L, both in complex with Gi. Our calculations allow todetect interactions between the R135L C-terminal tail with Gi that most likelyaffect the down-stream signalling pathway. These results providestructure-based explanations of the impairment of some key processes that leadto adRP.<!-- /* Font Definitions */@font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face{font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-alt:Calibri;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-520092929 1073786111 9 0 415 0;}@font-face{font-family:Cambria;panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin-top:0cm;margin-right:0cm;margin-bottom:8.0pt;margin-left:0cm;line-height:107%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:Calibri;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-GB;mso-fareast-language:EN-US;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-size:11.0pt;mso-ansi-font-size:11.0pt;mso-bidi-font-size:11.0pt;font-family:Calibri;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-fareast-language:EN-US;}.MsoPapDefault{mso-style-type:export-only;margin-bottom:8.0pt;line-height:107%;}size:612.0pt 792.0pt;margin:70.85pt 3.0cm 70.85pt 3.0cm;mso-header-margin:36.0pt;mso-footer-margin:36.0pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}