Modulation of CRX Transactivation Activity by Phosducin Isoforms

Zhu, Xuemei; Craft, Cheryl M.

doi:10.1128/mcb.20.14.5216-5226.2000

Cited by 63 publications

(66 citation statements)

References 63 publications

(92 reference statements)

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“…This hypothesis is based on the observations that 1) the phosducin C-terminal domain of 40 amino acid residues could serve as a transcriptional activator in both yeast and mammalian cells (42), 2) phosducin interacts with the photoreceptor-specific transcription factor CRX in vitro (43), and 3) a fraction of phosducin is present in the nuclei of bovine rods (27). In the next study using the phosducin knockout mouse we plan to analyze the reduction in transducin ␤␥ subunits in the context of either its reduced synthesis or its enhanced proteolysis.…”

Section: Discussionmentioning

confidence: 99%

Phosducin Facilitates Light-driven Transducin Translocation in Rod Photoreceptors

Sokolov

Strissel

Leskov

et al. 2004

Journal of Biological Chemistry

108

168

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Phosducin is a photoreceptor-specific protein known to interact with the ␤␥ subunits of G proteins. In pursuit of the function of phosducin, we tested the hypothesis that it regulates the light-driven translocation of G protein transducin from the outer segments of rod photoreceptors to other compartments of the rod cell. Transducin translocation has been previously shown to contribute to rod adaptation to bright illumination, yet the molecular mechanisms underlying the translocation phenomenon remain unknown. In this study we provide two major lines of evidence in support of the role of phosducin in transducin translocation. First, we have demonstrated that transducin ␤␥ subunits interact with phosducin along their entire intracellular translocation route, as evident from their co-precipitation in serial tangential sections from light-adapted but not darkadapted retinas. Second, we generated a phosducin knockout mouse and found that the degree of lightdriven transducin translocation in the rods of these mice was significantly reduced as compared with that observed in the rods of wild type animals. In knockout animals the translocation of transducin ␤␥ subunits was affected to a larger degree than the translocation of the ␣ subunit. We also found that the amount of phosducin in rods is sufficient to interact with practically all of the transducin present in these cells and that the subcellular distribution of phosducin is consistent with that of a soluble protein evenly distributed throughout the entire rod cytoplasm. Together, these data indicate that phosducin binding to transducin ␤␥ subunits facilitates transducin translocation. We suggest that the mechanism of phosducin action is based on the reduction of transducin affinity to the membranes of rod outer segments, achieved by keeping the transducin ␤␥ subunits apart from the ␣ subunit. This increased solubility of transducin would make it more susceptible to translocation from the outer segments.Vertebrate photoreceptors are highly specialized neurons responsible for the reception and primary processing of visual information. The outer segment compartment of the photoreceptor contains large amounts of the proteins involved in light detection and in the generation of the visual signal (for review, see Refs. 1-4). Photons entering the outer segment are absorbed by rhodopsin, which triggers sequential activation of many molecules of the photoreceptor-specific heterotrimeric G protein, transducin. Transducin activation consists of GTP binding to its ␣ subunit followed by dissociation of the ␣ subunit from the transducin ␤␥ subunits and the subsequent stimulation of the downstream effector, cGMP phosphodiesterase. Signaling persists until GTP is hydrolyzed and transducin subunits re-associate into a heterotrimer. In dark-adapted rods most of the transducin is located in the outer segments. However, prolonged exposures to bright light cause massive transducin translocation from rod outer segments to other subcellular compartments of the rod (5-10). In a recent st...

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Section: Discussionmentioning

confidence: 99%

Phosducin Facilitates Light-driven Transducin Translocation in Rod Photoreceptors

Sokolov

Strissel

Leskov

et al. 2004

Journal of Biological Chemistry

108

168

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“…Another idea that has been forwarded is that Pdc might play a role in the nucleus. A small fraction of the total Pdc appears to be localized in the nucleus [45,59], a Pdc C-terminal fragment has been reported to act as a transcription activator [60] and Pdc binds to the photoreceptor-specific transcription factor CRX in vitro [61]. In addition, Pdc has recently been shown to be SUMOylated and SUMOylation machinery has been shown to associate with the nuclear pore complex that imports proteins into the nucleus [50].…”

Section: Current Thinking -Pdc As a Chaperone Of Light-dependent G T mentioning

confidence: 99%

Function of phosducin-like proteins in G protein signaling and chaperone-assisted protein folding

Willardson

Howlett

2007

Cellular Signalling

101

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Members of the phosducin gene family were initially proposed to act as down-regulators of G protein signaling by binding G protein βγ dimers (Gβγ) and inhibiting their ability to interact with G protein α subunits (Gα) and effectors. However, recent findings have overturned this hypothesis by showing that most members of the phosducin family act as cochaperones with the cytosolic chaperonin complex (CCT) to assist in the folding of a variety of proteins from their nascent polypeptides. In fact rather than inhibiting G protein pathways, phosducin-like protein 1 (PhLP1) has been shown to be essential for G protein signaling by catalyzing the folding and assembly of the Gβγ dimer. PhLP2 and PhLP3 have no role in G protein signaling, but they appear to assist in the folding of proteins essential in regulating cell cycle progression as well as actin and tubulin. Phosducin itself is the only family member that does not participate with CCT in protein folding, but it is believed to have a specific role in visual signal transduction to chaperone Gβγ subunits as they translocate to and from the outer and inner segments of photoreceptor cells during light-adaptation.

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“…The fluorescence anisotropy decays of all five tryptophans revealed three classes of correlation times. Short correlation times located around 0.3-0.9 ns (␤ 1 ) and 1.4 -3.0 ns (␤ 2 ) reflect the fast local motions of tryptophan residues, and the third correlation time, 3 , likely reflects the rotational diffusion of the whole molecule. Changes in the extent of segmental motion of inserted tryptophans can be judged from the change in the sum of amplitudes of fast anisotropy decay components…”

Section: Conformational Behavior Of Pdc and Its Changes Upon Phosphormentioning

confidence: 99%

“…In addition, it has also been speculated that the 14-3-3 protein binding decreases the rate of Pdc dephosphorylation after a light stimulus by virtue of its interaction with phosphorylated Ser 54 and Ser 73 , thus lengthening the time that Pdc remains phosphorylated after a light exposure and/or stabilizes the N-terminal domain and protects phosphorylated Pdc from degradation (9). Yet another role for the 14-3-3 protein binding might be in the regulation of Pdc interaction with other proteins, including the SUG1 subunit of the proteasome complex and the transcription factor CRX (3,16). More detailed structural data on Pdc, of which the unbound (apo) structure is unknown, and its complex with the 14-3-3 protein are clearly needed to better understand the role of 14-3-3 in the regulation of Pdc function.…”

Section: Phosducin (Pdc)mentioning

confidence: 99%

“…3 is a highly conserved phosphoprotein involved in the regulation of visual signal transduction, transcriptional control, regulation of transmission at the photoreceptor-to-ON-bipolar cell synapse, and modulation of sympathetic activity and blood pressure (1)(2)(3)(4)(5). Other members of the Pdc protein family, Pdc-like proteins, act as co-chaperons and assist in the folding of a variety of proteins (6).…”

Section: Phosducin (Pdc)mentioning

confidence: 99%

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Structural Characterization of Phosducin and Its Complex with the 14-3-3 Protein

Kacirova

Košek

Kádek

et al. 2015

Journal of Biological Chemistry

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Background: Phosducin is a conserved regulatory phosphoprotein involved in phototransduction whose function is regulated in a 14-3-3-dependent manner. Results: The 14-3-3 protein binding affects the structure and the accessibility of several regions within both domains of phosphorylated phosducin. Conclusion: The 14-3-3 protein sterically occludes the whole G t ␤␥ binding interface of phosducin. Significance: Mechanistic explanation is given for the 14-3-3-dependent inhibition of phosducin function.

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Modulation of CRX Transactivation Activity by Phosducin Isoforms

Cited by 63 publications

References 63 publications

Phosducin Facilitates Light-driven Transducin Translocation in Rod Photoreceptors

Phosducin Facilitates Light-driven Transducin Translocation in Rod Photoreceptors

Function of phosducin-like proteins in G protein signaling and chaperone-assisted protein folding

Structural Characterization of Phosducin and Its Complex with the 14-3-3 Protein

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