Systematic protein–protein interaction mapping for clinically relevant human <scp>GPCR</scp>s

Sokolina, Kate; Kittanakom, Saranya; Snider, Jamie; Kotlyar, Max; Maurice, Pascal; Gandía, Jorge; Benleulmi-Chaachoua, Abla; Tadagaki, Kenjiro; Oishi, Atsuro; Wong, Victoria; Malty, Ramy H.; Deineko, Viktor; Aoki, Hiroyuki; Amin, Shahreen; Yao, Zhong; Morató, Xavier; Otasek, David; Kobayashi, Hiroyuki; Menéndez, Javier; Auerbach, Daniel; Angers, Stéphane; Pržulj, Nataša; Bouvier, Michel; Babu, Mohan; Ciruela, Francisco; Jockers, Ralf; Jurišica, Igor; Štagljar, Igor

doi:10.15252/msb.20167430

Cited by 66 publications

(66 citation statements)

References 91 publications

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“…1b). To confirm these predictions for human REEP5, we employed a membrane yeast two-hybrid (MYTH) system, as previously described 27,28 (Fig. 1c); which takes advantage of the ability of ubiquitin fragments (NubG and NubI) reconstitution, N-terminal TF transcription factor tagged (TF-Cub) bait protein and ubiquitin fragments tagged (NubI) prey protein were tested for protein-protein interactions.…”

Section: Resultsmentioning

confidence: 99%

REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects

et al. 2020

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The sarco-endoplasmic reticulum (SR/ER) plays an important role in the development and progression of many heart diseases. However, many aspects of its structural organization remain largely unknown, particularly in cells with a highly differentiated SR/ER network. Here, we report a cardiac enriched, SR/ER membrane protein, REEP5 that is centrally involved in regulating SR/ER organization and cellular stress responses in cardiac myocytes. In vitro REEP5 depletion in mouse cardiac myocytes results in SR/ER membrane destabilization and luminal vacuolization along with decreased myocyte contractility and disrupted Ca 2+ cycling. Further, in vivo CRISPR/Cas9-mediated REEP5 loss-of-function zebrafish mutants show sensitized cardiac dysfunction upon short-term verapamil treatment. Additionally, in vivo adeno-associated viral (AAV9)-induced REEP5 depletion in the mouse demonstrates cardiac dysfunction. These results demonstrate the critical role of REEP5 in SR/ER organization and function as well as normal heart function and development.

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Section: Resultsmentioning

confidence: 99%

REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects

et al. 2020

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“…This approach is bolstered by the fact that surveys of protein-protein interactions have revealed many interactions that, when disrupted, are deleterious. [39][40][41][42][43][44] Moreover, protein interactions can reveal defects in protein folding and stability, which helps to explain why approximately one-third of disease-related variants in proteins with multiple interaction partners disrupt all of the interactions of that protein. 45 Variants of protein-coding genes can also result in pathogenicity by altering splicing.…”

Section: Annotating Every Possible Variant In Disease-related Functiomentioning

confidence: 99%

Variant Interpretation: Functional Assays to the Rescue

Starita

Ahituv

Dunham

et al. 2017

The American Journal of Human Genetics

305

294

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Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of ''lookup tables'' of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis.

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“…In addition to the above-mentioned effectors, GPCRs also have numerous other interacting partners. These proteins can be either plasma membrane proteins such as ion channels, transporters, various serine/threonine-specific protein kinases, cytoskeletal proteins, Src homology and PDZ domain-containing proteins, small G proteins or extracellularly located adhesion molecules [32]. Accordingly, AT 1 R was shown to interact with wide spectra of other proteins beside G proteins and β-arrestins, such as AT 1 R-associated protein (ATRAP), phospholipase Cγ, JAK2 or other GPCRs, just to name a few, which may also take important parts in the complex pleiotropic effects of AT 1 R in the target tissues of the reninangiotensin system (RAS) [1].…”

Section: Signal Transducers Of At 1 Rmentioning

confidence: 99%

Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

Tóth

Turu

Hunyady

et al. 2018

Best Practice & Research Clinical Endocrinology & Metab

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AT angiotensin receptor (ATR), a prototypical G protein-coupled receptor (GPCR), is the main receptor, which mediates the effects of the renin-angiotensin system (RAS). ATR plays a crucial role in the regulation of blood pressure and salt-water homeostasis, and in the development of pathological conditions, such as hypertension, heart failure, cardiovascular remodeling, renal fibrosis, inflammation, and metabolic disorders. Stimulation of ATR leads to pleiotropic signal transduction pathways generating arrays of complex cellular responses. Growing amount of evidence shows that ATR is a versatile GPCR, which has multiple unique faces with distinct conformations and signaling properties providing new opportunities for functionally selective pharmacological targeting of the receptor. Biased ligands of ATR have been developed to selectively activate the β-arrestin pathway, which may have therapeutic benefits compared to the conventional angiotensin converting enzyme inhibitors and angiotensin receptor blockers. In this review, we provide a summary about the most recent findings and novel aspects of the ATR function, signaling, regulation, dimerization or oligomerization and its cross-talk with other receptors, including epidermal growth factor (EGF) receptor, adrenergic receptors and CB cannabinoid receptor. Better understanding of the mechanisms and structural aspects of ATR activation and cross-talk can lead to the development of novel type of drugs for the treatment of cardiovascular and other diseases.

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Systematic protein–protein interaction mapping for clinically relevant human GPCRs

Cited by 66 publications

References 91 publications

REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects

REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects

Variant Interpretation: Functional Assays to the Rescue

Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

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