In vivo differential prenylation of retinal cyclic GMP phosphodiesterase catalytic subunits.

Anant, Janmeet; Ong, Olivia C.; Xie, Hongying; Clarke, Steven; O’Brien, Paul; Fung, Bernard K.-K.

doi:10.1016/s0021-9258(18)48336-6

Cited by 198 publications

(14 citation statements)

References 40 publications

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“…20) imposed spatial restraints to the conformation of the ␣15 and ␣16 helices in our model that displaced these two helices toward the center of the catalytic domain (and are likely to contribute to the observed conformation of the H-and M-loops), as well as defining additional ␣-helical segments (C␣1 and C␣2) in the C-terminal region. The fact that the C termini of the PDE6 catalytic subunits are prenylated (25) and membrane-associated under our experimental conditions likely accounts for the structural differences we observe in the catalytic domain and C terminus. Together, these observations emphasize the importance of relying on this lower-resolution, chemical cross-linking/MS approach to define both flexible structural elements (e.g.…”

Section: Pde6 Holoenzyme Intra-and Intermolecular Cross-linked Peptidesmentioning

confidence: 79%

The molecular architecture of photoreceptor phosphodiesterase 6 (PDE6) with activated G protein elucidates the mechanism of visual excitation

Irwin

Gupta

Gao³

et al. 2019

Journal of Biological Chemistry

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Photoreceptor phosphodiesterase 6 (PDE6) is the central effector of the visual excitation pathway in both rod and cone photoreceptors, and PDE6 mutations that alter PDE6 structure or regulation can result in several human retinal diseases. The rod PDE6 holoenzyme consists of two catalytic subunits (P␣␤) whose activity is suppressed in the dark by binding of two inhibitory ␥-subunits (P␥). Upon photoactivation of rhodopsin, the heterotrimeric G protein (transducin) is activated, resulting in binding of the activated transducin ␣-subunit (Gt ␣ ) to PDE6, displacement of P␥ from the PDE6 active site, and enzyme activation. Although the biochemistry of this pathway is understood, a lack of detailed structural information about the PDE6 activation mechanism hampers efforts to develop therapeutic interventions for managing PDE6-associated retinal diseases. To address this gap, here we used a cross-linking MS-based approach to create a model of the entire interaction surface of P␥ with the regulatory and catalytic domains of P␣␤ in its nonactivated state. Following reconstitution of PDE6 and activated Gt ␣ with liposomes and identification of cross-links between Gt ␣ and PDE6 subunits, we determined that the PDE6 -Gt ␣ protein complex consists of two Gt ␣ -binding sites per holoenzyme. Each Gt ␣ interacts with the catalytic domains of both catalytic subunits and induces major changes in the interaction sites of the P␥ subunit with the catalytic subunits. These results provide the first structural model for the activated state of the transducin-PDE6 complex during visual excitation, enhancing our understanding of the molecular etiology of inherited retinal diseases.

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Section: Pde6 Holoenzyme Intra-and Intermolecular Cross-linked Peptidesmentioning

confidence: 79%

The molecular architecture of photoreceptor phosphodiesterase 6 (PDE6) with activated G protein elucidates the mechanism of visual excitation

Irwin

Gupta

Gao³

et al. 2019

Journal of Biological Chemistry

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“…It is interesting to note that AIPL1 plays an essential role in processing of farnesylated proteins in retina (27). The carboxyterminus of PDE6A is farnesylated (28), and this modification is necessary for proper anchoring of the PDE6 complex to the OSs (29). Presumably, the observed changes in cGMP levels in Aipl1 mutants are in part due to its role in generating a fully functional PDE6 protein complex localized to the OSs.…”

Section: Discussionmentioning

confidence: 99%

New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene

Sakamoto

McCluskey

Wensel

et al. 2008

Human Molecular Genetics

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The heterotetrameric phosphodiesterase (PDE) 6 complex, made up of a, b and two g subunits, regulates intracellular cGMP levels by hydrolyzing cGMP in response to light activation of G protein coupled receptors in cones and rods, making it an essential component of the visual phototransduction cascade [Zhang, X. and Cote, R.H. ( 2005) cGMP signaling in vertebrate retinal photoreceptor cells. Front. Biosci., 10, 1191 -1204.]. Using a genetic positional candidate cloning strategy, we have identified missense mutations within the catalytic domain of the Pde6a gene in two mouse models from an ethyl nitrosourea chemical mutagenesis screen. In these first small rodent models of PDE6A, significantly different biochemical outcomes and rates of degeneration of murine photoreceptor cells were observed, indicating allelic variation and previously unrecognized structure -function relationships. In addition, these new models reveal that the mutations not only affect the function of the PDE6A protein itself, but also the level of PDE6B within the retina. Finally, we show that the variation of the disease phenotype by background modifier genes may be dependent upon the particular disease allele present.

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“…PDE is bound through the isoprenylated carboxy termini of the catalytic a and p subunits to rod disc membranes (Qin, Pittler, and Baehr, 1992;Anant et al, 1992). The isoprenylated membrane-bound PDE is recognised and solubilised by PDE5 under physiological conditions .…”

Section: 61viii -Cone Pigmentsmentioning

confidence: 99%

Identification of a novel protein interacting with RPGR

Boylan

2000

Human Molecular Genetics

113

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A novel protein, called RPGRIP, has been identified as interacting with the RPGR protein, which is mutated in a severe form of human retinal degeneration, X-linked retinitis pigmentosa (RP3 type). The bovine RPGRIP was identified initially by screening for RPGR-interacting proteins with a bovine retina cDNA library using the yeast two-hybrid system. The specificity of the interaction was confirmed by co-immunoprecipitation of in vitro translated protein and using RPGR mutants. The human RPGRIP gene was isolated and shown to be expressed in retina and testis. Human RPGRIP spans a genomic interval of 34 kb, and consists of 15 exons, some of which are alternatively spliced. It was mapped using monochromosomal and radiation hybrid cell lines to chromosomal region 14q11. The function of RPGRIP is unknown; it shows no homology to proteins of known function, although it is predicted to form two coiled-coil domains at the N-terminus. RPGRIP is a strong candidate gene for causing human retinal degeneration.

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In vivo differential prenylation of retinal cyclic GMP phosphodiesterase catalytic subunits.

Cited by 198 publications

References 40 publications

The molecular architecture of photoreceptor phosphodiesterase 6 (PDE6) with activated G protein elucidates the mechanism of visual excitation

The molecular architecture of photoreceptor phosphodiesterase 6 (PDE6) with activated G protein elucidates the mechanism of visual excitation

New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene

Identification of a novel protein interacting with RPGR

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