G Proteins and Phototransduction

Arshavsky, Vadim Y.; Lamb, Trevor D; Pugh, Edward N.

doi:10.1146/annurev.physiol.64.082701.102229

Cited by 581 publications

(490 citation statements)

References 129 publications

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“…As part of the phototransduction signaling pathway, Gα t ·GTP activates PDE6 by binding directly to PDEγ and releasing the inhibitory constraint which PDEγ imposes on the α and β catalytic subunits of PDE6 (41).We tested whether KB-1753 could impair PDE6 activation by Gα t ·GTP by measuring the steady-state rate of cGMP degradation to GMP. Rhodopsin-activated transducin was observed to stimulate degradation of cGMP in reconstituted ROS membranes ( Figure 4C).…”

Section: Kb-1753 Blocks Gα/effector Interactionmentioning

confidence: 99%

Minimal Determinants for Binding Activated Gα from the Structure of a Gα_i1−Peptide Dimer^,

et al. 2006

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G-proteins cycle between an inactive GDP-bound state and active GTP-bound state, serving as molecular switches that coordinate cellular signaling. We recently used phage-display to identify a series of peptides that bind Gα subunits in a nucleotide-dependent manner [Johnston, C. A., Willard, F. S., Jezyk, M. R., Fredericks, Z., Bodor, E. T., Jones, M. B., Blaesius, R., Watts, V. J., Harden, T. K., Sondek, J., Ramer, J. K., and Siderovski, D. P. (2005) Structure 13, 1069-1080]. Here we describe the structural features and functions of KB-1753, a peptide that binds selectively to GDP·AlF 4 − -and GTPγS-bound states of Gα i subunits. KB-1753 blocks interaction of Gα transducin with its effector, cGMP phosphodiesterase, and inhibits transducin-mediated activation of cGMP degradation. Additionally, KB-1753 interferes with RGS protein binding and resultant GAP activity. A fluorescent KB-1753 variant was found to act as a sensor for activated Gα in vitro. The crystal structure of KB-1753 bound to Gα i1 ·GDP·AlF 4 − reveals binding to a conserved hydrophobic groove between switch II and α3 helices, and, along with supporting biochemical data and previous structural analyses, supports the notion that this is the site of effector interactions for Gα i subunits.Heterotrimeric G-proteins serve as critical relays that transmit cues from extracellular stimuli as diverse as neurotransmitters, hormones, photons, and odorants/tastants to intracellular signaling cascades responsible for eliciting specific cellular effects (1,2). In the traditional model of G-protein signaling, cell surface G-protein coupled receptors (GPCRs), upon activation by the aforementioned stimuli, catalyze the exchange of GDP for GTP on the Gα *To whom correspondence should be addressed: UNC Pharmacology, 1106 M.E. Jones Bldg., Chapel Hill, NC 27599-7365. Telephone: 919-843-9363. Fax: 919-966-5640. E-mail: dsiderov@med.unc.edu. Current addresses: Entegrion, 5312 Farrington Rd., Chapel Hill, NC 27517 (J.K.R); Becton Dickinson, 21 Davis Dr., RTP, NC 27709 (R.B.); Amgen Inc., 1201 Amgen Court W., Seattle, WA 98119 (Z.F.). † This work was supported by NIH R01 GM074268 (D.P.S.) and EY12859 (V.Y.A.). C.A.J. was supported by an NIH postdoctoral fellowship (1 F32 GM076944). V.Y.A. is the recipient of the Senior Scientific Investigator Award from Research to Prevent Blindness Inc. Coordinates of the KB-1753/Gα i1 ·GDP·AlF 4 − complex were deposited in the Protein Data Bank (accession code 2G83). 1 Abbreviations: AlF 4 − , aluminum tetrafluoride; CFP, cyan fluorescent protein; cGMP, cyclic guanosine monophosphate; FRET, fluorescence resonance energy transfer; GAP, GTPase-accelerating protein; GDP, guanosine diphosphate; GEF, guanine nucleotide exchange factor; GMP, guanosine monophosphate; GPCR, G protein-coupled receptor; GTP, guanosine triphosphate; PDE, phosphodiesterase; RGS, regulator of G-protein signaling; ROS, rod outer segment; SPR, surface plasmon resonance; YFP, yellow fluorescent protein. subunit. This results in adoption of the active, GTP-bou...

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Section: Kb-1753 Blocks Gα/effector Interactionmentioning

confidence: 99%

Minimal Determinants for Binding Activated Gα from the Structure of a Gα_i1−Peptide Dimer^,

et al. 2006

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“…Eukaryotic cells use G protein signaling systems to mediate a wide array of hormonal, neuronal and sensory signals that control numerous physiological processes ranging from cardiac rhythm [1] to psychological behavior [2] to vision [3]. The importance of G protein signaling to cellular physiology is evidenced by the large number of genes encoding GPCRs (∼ 800 in humans [4]) and the myriad of diseases linked to malfunctions in G protein signaling [5].…”

Section: Introductionmentioning

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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“…Light initiates phototransduction by activating rhodopsin, which then transmits and amplifies the signal by activating the visual G-protein transducin (Tr) (Burns and Baylor, 2001;Arshavsky et al, 2002). Termination of the light signal requires that light-activated rhodopsin is deactivated by incorporation of multiple phosphates at its C terminus by rhodopsin kinase (RK) (Wilden et al, 1986;Chen et al, 1999a;Mendez et al, 2000) and the subsequent binding of arrestin (Arr).…”

Section: Introductionmentioning

confidence: 99%

Light-Dependent Translocation of Arrestin in the Absence of Rhodopsin Phosphorylation and Transducin Signaling

2003

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Visual arrestin plays a crucial role in the termination of the light response in vertebrate photoreceptors by binding selectively to lightactivated, phosphorylated rhodopsin. Arrestin localizes predominantly to the inner segments and perinuclear region of dark-adapted rod photoreceptors, whereas light induces redistribution of arrestin to the rod outer segments. The mechanism by which arrestin redistributes in response to light is not known, but it is thought to be associated with the ability of arrestin to bind photolyzed, phosphorylated rhodopsin in the outer segment. In this study, we show that light-driven translocation of arrestin is unaffected in two different mouse models in which rhodopsin phosphorylation is lacking. We further show that arrestin movement is initiated by rhodopsin but does not require transducin signaling. These results exclude passive diffusion and point toward active transport as the mechanism for lightdependent arrestin movement in rod photoreceptor cells.

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G Proteins and Phototransduction

Cited by 581 publications

References 129 publications

Minimal Determinants for Binding Activated Gα from the Structure of a Gα_i1−Peptide Dimer^,

Minimal Determinants for Binding Activated Gα from the Structure of a Gα_i1−Peptide Dimer^,

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

Light-Dependent Translocation of Arrestin in the Absence of Rhodopsin Phosphorylation and Transducin Signaling

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G Proteins and Phototransduction

Cited by 581 publications

References 129 publications

Minimal Determinants for Binding Activated Gα from the Structure of a Gαi1−Peptide Dimer,

Minimal Determinants for Binding Activated Gα from the Structure of a Gαi1−Peptide Dimer,

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

Light-Dependent Translocation of Arrestin in the Absence of Rhodopsin Phosphorylation and Transducin Signaling

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Minimal Determinants for Binding Activated Gα from the Structure of a Gα_i1−Peptide Dimer^,

Minimal Determinants for Binding Activated Gα from the Structure of a Gα_i1−Peptide Dimer^,