Membrane Protein Transport in Photoreceptors: The Function of PDE{delta} [Lectures]

This lecture details the elucidation of cGMP phosphodiesterase (PDE), discovered 25 years ago by Joe Beavo at the University of Washington. PDE, once identified as a fourth PDE6 subunit, is now regarded as a promiscuous prenyl-binding protein and important chaperone of prenylated small G proteins of the Ras superfamily and prenylated proteins of phototransduction. Alfred Wittinghofer's group in Germany showed that PDE forms an immunoglobulin-like β-sandwich fold that is closely related in structure to other lipid-binding proteins, for example, Uncoordinated 119 (UNC119) and RhoGDI. His group cocrystallized PDE with ARL (Arf-like) 2GTP, and later with farnesylated Rheb (ras homolog expressed in brain). PDE specifically accommodates farnesyl and geranylgeranyl moieties in the absence of bound protein. Germline deletion of the Pde6d gene encoding PDE impeded transport of rhodopsin kinase (GRK1) and PDE6 to outer segments, causing slowly progressing, recessive retinitis pigmentosa. A rare PDE6D null allele in human patients, discovered by Tania Attié-Bitach in France, specifically impeded trafficking of farnesylated phosphatidylinositol 3,4,5-trisphosphate (PIP3) 5-phosphatase (INPP5E) to cilia, causing severe syndromic ciliopathy (Joubert syndrome). Binding of cargo to PDE is controlled by Arf-like proteins, ARL2 and ARL3, charged with guanosine-5'-triphosphate (GTP). Arf-like proteins 2 and 3 are unprenylated small GTPases that serve as cargo displacement factors. T...
Source: Investigative Ophthalmology - Category: Opthalmology Authors: Tags: Lectures Source Type: research