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Review
. 2012 Dec 15:75:19-25.
doi: 10.1016/j.visres.2012.08.013. Epub 2012 Aug 29.

The prenyl-binding protein PrBP/δ: a chaperone participating in intracellular trafficking

Houbin Zhang  1 , Ryan Constantine, Jeanne M Frederick, Wolfgang Baehr
Affiliations
Review

The prenyl-binding protein PrBP/δ: a chaperone participating in intracellular trafficking

Houbin Zhang et al. Vision Res. .

Abstract

Expressed ubiquitously, PrBP/δ functions as chaperone/co-factor in the transport of a subset of prenylated proteins. PrBP/δ features an immunoglobulin-like β-sandwich fold for lipid binding, and interacts with diverse partners. PrBP/δ binds both C-terminal C15 and C20 prenyl side chains of phototransduction polypeptides and small GTP-binding (G) proteins of the Ras superfamily. PrBP/δ also interacts with the small GTPases, ARL2 and ARL3, which act as release factors (GDFs) for prenylated cargo. Targeted deletion of the mouse Pde6d gene encoding PrBP/δ resulted in impeded trafficking to the outer segments of GRK1 and cone PDE6 which are predicted to be farnesylated and geranylgeranylated, respectively. Rod and cone transducin trafficking was largely unaffected. These trafficking defects produce progressive cone-rod dystrophy in the Pde6d(-/-) mouse.

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Figures

Figure 1
Figure 1
Dendrogram of 21 PrBP/δ orthologs. Amino acid sequences were retrieved using the accession numbers shown, and aligned using ClustalW. The dendrogram was generated from the alignment. Sequences among vertebrates are highly conserved. PrBP/δ sequences of C. elegans and human are 65% similar suggesting conserved function through evolution.
Figure 2
Figure 2
CAAX-Protein prenylation and processing (example: PDE6α). After prenylation in the cytosol, PDE6α protein docks at the ER and undergoes enzymatic processing by RCE1P protease that removes AAX, and an S-adenosylmethionine-dependent methyltransferase (ICMT) that carboxymethylates the C-terminal cysteine.
Figure 3
Figure 3
PDE6 may be membrane-bound or soluble. A, Schematic of PDE6αβγγ bound to ROS disc membranes via prenyl side chains. B, Association of PDE6αβγγ with PrBP/δ (delta) forms a soluble and diffusible complex. C, Structure of soluble PDE6αβγγδδ by Cryo-EM at 18 Å resolution in two orientations (Goc et al., 2010).
Figure 4
Figure 4
Function and sequence comparison of human and C. elegans PrBP/δ. A, Extraction of PDE6 as a function of human PrBP/δ versus its ortholog expressed in C. elegans. B, Sequence alignment of human PrBP/δ (1) and C. elegans PrBP/δ (2) (Li and Baehr, 1998).
Figure 5
Figure 5
Ribbon representation of the PrBP/δ-Arl2/GTP complex (PDB 1KSH). GTP (shown as sticks in dark blue) is bound to Arl2. Arl2 blocks the entrance (arrow) through which the lipid side chain of prenylated proteins may insert. Figure was created with PyMOL (www.pymol.org).
Figure 6
Figure 6
Structure of the Rheb(GDP)-PrBP/δ complex. Top, structure modified from Ismail, et al. (PDB 3T5I). The C-terminal farnesyl chain of Rheb (green) is inserted into the β-sandwich structure of PrBP/δ. GDP (dark gray) of Rheb is shown. Bottom, the structure of PrBP/δ with inserted farnesyl (green). Cys (yellow) of Rheb is shown. The middle and right structures were generated by 90° counterclockwise rotation.
Figure 7
Figure 7
ARL3-GTP functions as a GDF (GDI-displacement factor). Top, Step1: Rheb is extracted from membrane 1 by PrBP/δ, Step 2: an intermediate ternary complex is formed with ARL3-GTP. Step 3: Rheb is displaced to membrane 2 by ARL3-GTP acting as a GDF. The cycle is completed by the ARL3 GAP, RP2, which produces ARL3-GDP and free PrBP/δ.
Figure 8
Figure 8
PrBP/δ-dependent export of PDE6 and GRK1 from the ER in rods. A, GRK1 and PDE6αβ dock to the ER after prenylation and processing. Prenylated proteins may be extracted from the ER by PrBP/δ (δ, purple) forming a diffusible complex. Additional prenyl binding proteins likely exist (X, in black). Transfer from ER (membrane 1) to the transport vesicle (membrane 2) is likely mediated by ARL2/3 functioning as a GDF, as outlined in Fig. 7. B, Deletion of PrBP/δ prevents GRK1 exit from the ER. With the help of X, PDE6 still travels to the OS although some PDE6 is retained and mislocalized in the inner segment (Zhang et al., 2007). This model is based on (Zhang et al., 2007; Baehr et al., 2007; Karan et al., 2008).
Figure 9
Figure 9
PrBP/δ-dependent transport in cones. A, Processing of cone PDE6 and GRK1 in WT cones. Cone PDE6 consists of two identical geranylgeranylated subunits (PDEα′). Both are thought to interact with PrBP/δ. B, Deletion of PrBP/δ prevents trafficking of cone PDE6 subunits and GRK1 to the outer segments. Prenylated subunits, unable to exit the ER, are presumably degraded.
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