G Protein-Coupled Receptors Contain Two Conserved Packing Clusters

Sánchez-Reyes, Omar B.; Cooke, Aidan L.G.; Tranter, Dale; Rashid, Dawood; Eilers, Markus; Reeves, Philip J.; Smith, Steven O.

doi:10.1016/j.bpj.2017.04.051

Cited by 20 publications

(33 citation statements)

References 64 publications

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“…In nonolfactory class A GPCRs, position 4.53 is conserved as S39%, A33%, V8%, T4%, C3.5%, P3%, G3%, I2%, and M1.5%, and position 5.47 is conserved as F65%, Y11%, L10%, N3.5%, V3%, G2%, I2%, and C2%. Position 4.53, as well as position 2.47, has been identified as a conserved packing cluster center in class A GPCRs, and its mutation in leucine (A 4.53 L) in Rhodopsin disrupts the structure of the receptor (42). In the β2-adrenergic receptor, S 4.53 belong to the motif S 4.53 xxxS 4.57 which does not participate to the functionality of the receptor and seems to be more involved in helix packing, maintaining the stability of the receptor (43).…”

Section: Discussionmentioning

confidence: 99%

Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

Ikegami

March

Nagai

et al. 2020

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

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Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in nonolfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing consensus odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations.

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Section: Discussionmentioning

confidence: 99%

Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

Ikegami

March

Nagai

et al. 2020

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

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“…H211P) or introduce bulky side chains into regions of tight helix packing. Crystal structures reveal the 7TM bundle of rhodopsin contains both tightly packed and more loosely packed helices (Sanchez-Reyes et al, 2017). Two separate interior packing clusters (1&2) were identified that mediate interactions between TM helices H1 and H2 or H3 and H4 respectively.…”

Section: Structural and Biochemical Basis Of Rhodopsin Rp Mutantsmentioning

confidence: 99%

“…These packing clusters are conserved in GPCRs and are composed of amino acids with small side chains. The residue A164 is a component of packing cluster 2 and presumably its mutation to a more bulky valine (A164V) could disturb rhodopsin folding and stability by disrupting formation of this packing core leading to misfolding (Sanchez-Reyes et al, 2017; Stojanovic et al, 2003).…”

Section: Structural and Biochemical Basis Of Rhodopsin Rp Mutantsmentioning

confidence: 99%

The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy

Athanasiou¹,

Aguilà²,

Bellingham³

et al. 2018

Progress in Retinal and Eye Research

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277

328

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Inherited mutations in the rod visual pigment, rhodopsin, cause the degenerative blinding condition, retinitis pigmentosa (RP). Over 150 different mutations in rhodopsin have been identified and, collectively, they are the most common cause of autosomal dominant RP (adRP). Mutations in rhodopsin are also associated with dominant congenital stationary night blindness (adCSNB) and, less frequently, recessive RP (arRP). Recessive RP is usually associated with loss of rhodopsin function, whereas the dominant conditions are a consequence of gain of function and/or dominant negative activity. The in-depth characterisation of many rhodopsin mutations has revealed that there are distinct consequences on the protein structure and function associated with different mutations. Here we categorise rhodopsin mutations into seven discrete classes; with defects ranging from misfolding and disruption of proteostasis, through mislocalisation and disrupted intracellular traffic to instability and altered function. Rhodopsin adRP offers a unique paradigm to understand how disturbances in photoreceptor homeostasis can lead to neuronal cell death. Furthermore, a wide range of therapies have been tested in rhodopsin RP, from gene therapy and gene editing to pharmacological interventions. The understanding of the disease mechanisms associated with rhodopsin RP and the development of targeted therapies offer the potential of treatment for this currently untreatable neurodegeneration.

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“…In non-olfactory class A GPCRs, position 4.53 is conserved as S39%, A33%, V8%, T4%, C3.5%, P3%, G3%, I2%, M1.5% and position 5.47 is conserved as F65%, Y11%, L10%, N3.5%, V3%, G2%, I2%, C2%. Position 4.53, as well as position 2.47, has been identified as a conserved packing cluster center in class A GPCRs and its mutation in leucine (A 4.53 L) in Rhodopsin disrupts the structure of the receptor (41). In the β2-adrenergic receptor, S 4.53 belong to the motif S 4.53 xxxS 4.57 which doesn't participate to the functionality of the receptor and seems to be more involved in helix packing, maintaining the stability of the receptor (42).…”

Section: Discussionmentioning

confidence: 99%

Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

Ikegami

March

Nagai

et al. 2019

Preprint

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Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in non-olfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here, we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing "consensus" odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations. Significance StatementOdor detection in mammals depends on the largest family of G protein-coupled receptors, the odorant receptors, which represent ~2% of our protein-coding genes. The vast majority of odorant receptors are trapped within the cell when expressed in non-olfactory cells. The underlying causes of why odorant receptors cannot be functionally expressed in non-olfactory cells have remained enigmatic for over 20 years. Our study points to divergence from a

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G Protein-Coupled Receptors Contain Two Conserved Packing Clusters

Cited by 20 publications

References 64 publications

Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy

Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

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