Structural, Energetic, and Mechanical Perturbations in Rhodopsin Mutant That Causes Congenital Stationary Night Blindness

Kawamura, Shiho; Colozo, Alejandro T.; Ge, Lin; Müller, Daniel J.; Park, Paul S.‐H.

doi:10.1074/jbc.m112.340182

Cited by 27 publications

(78 citation statements)

References 47 publications

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“…The primary structural impact of replacing a Gly residue with the charged Asp residue appears to be a perturbation in the chromophore-binding pocket (Singhal et al, 2013). An altered chromophore-binding pocket is suggested by a blue-shifted λ max displayed by the mutant and a solvent accessible chromophore-binding pocket in the dark state of G90D rhodopsin (Kaushal & Khorana, 1994; Kawamura et al, 2012; Rao et al, 1994; Zvyaga, Fahmy, Siebert, & Sakmar, 1996). …”

Section: Constitutive Activty In Rhodopsin That Causes Diseasementioning

confidence: 99%

“…The mutant apoprotein can bind 11- cis retinal (Kawamura, Colozo, Ge, Muller, & Park, 2012; Sieving et al, 2001), albeit more slowly compared to the wild-type apoprotein (Gross, Xie, & Oprian, 2003; Toledo et al, 2011). The primary structural impact of replacing a Gly residue with the charged Asp residue appears to be a perturbation in the chromophore-binding pocket (Singhal et al, 2013).…”

Section: Constitutive Activty In Rhodopsin That Causes Diseasementioning

confidence: 99%

“…The dark state of G90D rhodopsin from heterologous expression systems exhibits some of the structural hallmarks of the active MII state, such as neutralization of Glu113 and movement of the cytoplasmic half of TM6 (Fahmy, Zvyaga, Sakmar, & Siebert, 1996; Kim et al, 2004; Zvyaga et al, 1996). Dark-state G90D rhodopsin embedded in native ROS membranes from transgenic mice also display characteristics expected for an active state (Kawamura et al, 2012). The constitutive activity in the dark-state mutant does not appear to be a result of thermal isomerization of bound 11- cis retinal (Dizhoor et al, 2008), but instead, likely related to the replacement of Glu113 by the mutant Asp residue as the counterion for the protonated Schiff base at Lys296 (Singhal et al, 2013).…”

Section: Constitutive Activty In Rhodopsin That Causes Diseasementioning

confidence: 99%

“…Blue-shifted λ max (480–485 nm) (S. Jager et al, 1997; Kaushal & Khorana, 1994; Kawamura et al, 2012; Rao et al, 1994; Zvyaga et al, 1996). …”

Section: Figurementioning

confidence: 99%

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Constitutively Active Rhodopsin and Retinal Disease

Park

2014

Advances in Pharmacology

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Rhodopsin is the light receptor in rod photoreceptor cells of the retina that initiates scotopic vision. In the dark, rhodopsin is bound to the chromophore 11-cis retinal, which locks the receptor in an inactive state. The maintenance of an inactive rhodopsin in the dark is critical for rod photoreceptor cells to remain highly sensitive. Perturbations by mutation or absence of 11-cis retinal can cause rhodopsin to become constitutively active, which leads to the desensitization of photoreceptor cells and, in some instances, retinal degeneration. Constitutive activity can arise in rhodopsin by various mechanisms and can cause a variety of inherited retinal diseases including Leber congenital amaurosis, congenital night blindness, and retinitis pigmentosa. In this review, the molecular and structural properties of different constitutively active forms of rhodopsin are overviewed and the possibility that constitutive activity can arise from different active-state conformations is discussed.

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Section: Constitutive Activty In Rhodopsin That Causes Diseasementioning

confidence: 99%

Section: Constitutive Activty In Rhodopsin That Causes Diseasementioning

confidence: 99%

Section: Constitutive Activty In Rhodopsin That Causes Diseasementioning

confidence: 99%

“…Blue-shifted λ max (480–485 nm) (S. Jager et al, 1997; Kaushal & Khorana, 1994; Kawamura et al, 2012; Rao et al, 1994; Zvyaga et al, 1996). …”

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Constitutively Active Rhodopsin and Retinal Disease

Park

2014

Advances in Pharmacology

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“…Such stable structural segments can represent single parts or combinations of secondary structural elements such as transmembrane α-helices, β-strands, or polypeptide loops. In the past, SMFS has been used to characterize interactions in membrane proteins induced by ligand or inhibitor binding (30)(31)(32)(33)(34), by signal transduction (35), by mutations (36)(37)(38), by oligomeric assemblies (39), or by the lipid composition of the bilayer membrane (40). In this work we applied SMFS to localize the interactions that stabilize structural segments of DtpA and to characterize the mechanisms an inhibitor uses to modulate the functional state of the peptide transporter.…”

Section: Significancementioning

confidence: 99%

Peptide transporter DtpA has two alternate conformations, one of which is promoted by inhibitor binding

Bippes

Meury

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Peptide transporters (PTRs) of the large PTR family facilitate the uptake of di-and tripeptides to provide cells with amino acids for protein synthesis and for metabolic intermediates. Although several PTRs have been structurally and functionally characterized, how drugs modulate peptide transport remains unclear. To obtain insight into this mechanism, we characterize inhibitor binding to the Escherichia coli PTR dipeptide and tripeptide permease A (DtpA), which shows substrate specificities similar to its human homolog hPEPT1. After demonstrating that Lys[Z-NO 2 ]-Val, the strongest inhibitor of hPEPT1, also acts as a high-affinity inhibitor for DtpA, we used single-molecule force spectroscopy to localize the structural segments stabilizing the peptide transporter and investigated which of these structural segments change stability upon inhibitor binding. This characterization was done with DtpA embedded in the lipid membrane and exposed to physiologically relevant conditions. In the unbound state, DtpA adopts two main alternate conformations in which transmembrane α-helix (TMH) 2 is either stabilized (in ∼43% of DtpA molecules) or not (in ∼57% of DtpA molecules). The two conformations are understood to represent the inward-and outward-facing conformational states of the transporter. With increasing inhibitor concentration, the conformation characterized by a stabilized TMH 2 becomes increasingly prevalent, reaching ∼92% at saturation. Our measurements further suggest that Lys[Z-NO 2 ]-Val interacts with discrete residues in TMH 2 that are important for ligand binding and substrate affinity. These interactions in turn stabilize TMH 2, thereby promoting the inhibited conformation of DtpA.membrane transporter | proton-dependent oligopeptide transporter | major facilitator superfamily | atomic force microscopy | molecular interactions

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Light Dynamics of the Retinal‐Disease‐Relevant G90D Bovine Rhodopsin Mutant

et al. 2020

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The RHO gene encodes the G‐protein‐coupled receptor (GPCR) rhodopsin. Numerous mutations associated with impaired visual cycle have been reported; the G90D mutation leads to a constitutively active mutant form of rhodopsin that causes CSNB disease. We report on the structural investigation of the retinal configuration and conformation in the binding pocket in the dark and light‐activated state by solution and MAS‐NMR spectroscopy. We found two long‐lived dark states for the G90D mutant with the 11‐cis retinal bound as Schiff base in both populations. The second minor population in the dark state is attributed to a slight shift in conformation of the covalently bound 11‐cis retinal caused by the mutation‐induced distortion on the salt bridge formation in the binding pocket. Time‐resolved UV/Vis spectroscopy was used to monitor the functional dynamics of the G90D mutant rhodopsin for all relevant time scales of the photocycle. The G90D mutant retains its conformational heterogeneity during the photocycle.

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Structural, Energetic, and Mechanical Perturbations in Rhodopsin Mutant That Causes Congenital Stationary Night Blindness

Cited by 27 publications

References 47 publications

Constitutively Active Rhodopsin and Retinal Disease

Constitutively Active Rhodopsin and Retinal Disease

Peptide transporter DtpA has two alternate conformations, one of which is promoted by inhibitor binding

Light Dynamics of the Retinal‐Disease‐Relevant G90D Bovine Rhodopsin Mutant

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