G protein | EPFL Graph Search

G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases. There are two classes of G proteins. The first function as monomeric small GTPases (small G-proteins), while the second function as heterotrimeric G protein complexes. The latter class of complexes is made up of alpha (α), beta (β) and gamma (γ) subunits. In addition, the beta and gamma subunits can form a stable dimeric complex referred to as the beta-gamma complex . Heterotrimeric G proteins located within the cell are activated by G protein-coup

Signaling downstream of the novel oncogene GNAQ in uveal melanoma

Lona Gaugler

[...] This report presents novel data following the discovery of somatic mutations in the heterotrimeric G protein alpha q subunit (GNAQ), found in 44% of uveal melanomas, 83% of blue nevi, and 50% of melanomas arising within blue nevi. [... click on "Download fulltext" for full abstract]

2008

Reprogramming G Protein-Coupled Receptor Structure, Function And Signaling By Computational Design

Dániel Kéri

G protein-coupled receptors (GPCRs) are 7-transmembrane alpha-helical integral membrane proteins on which cells heavily rely to receive information regarding their external environment. These receptors are able to transfer information to intracellular downstream effectors upon stimulation from their cognate ligands, which can be considerably diverse. They can include light, small molecules, peptides, protons; Due to its evolutionary success, over millions of years of evolution, this protein family has expanded to include over 800 members. Despite the large size of the family and the diverse inputs they accept, the structure and the mechanism for relaying signals to their downstream partners, G proteins and B-arrestins, remains largely the same. As these receptors are involved in a great deal of biological processes such as sight (rhodopsin), cognition (dopamine, serotonin, opioid receptors), immunity (chemokine receptors), heart function (adrenergic, angiotensin receptors), etc.; a great deal of effort has gone into understanding their structure and function. Our efforts have gone into understanding their signaling properties and rationally modifying them. Most proteins are fairly flexible entities and their structures tend to oscillate and move around, sampling a number of conformations. Nature has taken advantage of these natural motions to regulate protein function from distant binding sites, in a phenomenon called allostery. GPCRs are unique in the sense that their primary function relies on allostery. By tweaking the allosteric signaling of GPCRs, we hope to have a better understand allostery, use the principles we learn to create designer GPCR biosensors with the desired sensitivity, and to eventually create de novo allosteric proteins. In this work, I present our progress in this effort, which has been significant. We have created a highly accurate in silico method to allosterically alter relative stabilities of the active and inactive states of the GPCR dopamine D2 receptor, but also to independently control its allosteric signaling strength. With our methodology we have been able to create receptors which have high basal activities by selectively stabilizing the active state of the receptor. This has already facilitated the structure determination of the active, G protein-bound dopamine D2 receptor; a first for this GPCR. Additionally, we have created a number of dopamine D2 variants with roughly 100 times higher sensitivity to dopamine than the WT receptor. These efforts continue to characterize the functional effects of these allosteric mutations. Furthermore, we are also working on a collaboration to rewire the signaling pathway of the adenosine A2A receptor. Adenosine is a common immunosuppresant in solid tumor micro-environments (TMEs). By rewiring the downstream signaling of the A2A receptor, we hope to reverse the response of T-cells in these TMEs to activate and attack the solid tumor.

EPFL2021

MicroRNA-22 (miR-22) Overexpression Is Neuroprotective via General Anti-Apoptotic Effects and May also Target Specific Huntington's Disease-Related Mechanisms

Ana Jovicic

Background: Whereas many causes and mechanisms of neurodegenerative diseases have been identified, very few therapeutic strategies have emerged in parallel. One possible explanation is that successful treatment strategy may require simultaneous targeting of more than one molecule of pathway. A new therapeutic approach to have emerged recently is the engagement of microRNAs (miRNAs), which affords the opportunity to target multiple cellular pathways simultaneously using a single sequence. Methodology/Principal Findings: We identified miR-22 as a potentially neuroprotective miRNA based on its predicted regulation of several targets implicated in Huntington's disease (histone deacetylase 4 (HDAC4), REST corepresor 1 (Rcor1) and regulator of G-protein signaling 2 (Rgs2)) and its diminished expression in Huntington's and Alzheimer's disease brains. We then tested the hypothesis that increasing cellular levels of miRNA-22 would achieve neuroprotection in in vitro models of neurodegeneration. As predicted, overexpression of miR-22 inhibited neurodegeneration in primary striatal and cortical cultures exposed to a mutated human huntingtin fragment (Htt171-82Q). Overexpression of miR-22 also decreased neurodegeneration in primary neuronal cultures exposed to 3-nitropropionic acid (3-NP), a mitochondrial complex II/III inhibitor. In addition, miR-22 improved neuronal viability in an in vitro model of brain aging. The mechanisms underlying the effects of miR-22 included a reduction in caspase activation, consistent with miR-22's targeting the pro-apoptotic activities of mitogen-activated protein kinase 14/p38 (MAPK14/p38) and tumor protein p53-inducible nuclear protein 1 (Tp53inp1). Moreover, HD-specific effects comprised not only targeting HDAC4, Rcor1 and Rgs2 mRNAs, but also decreasing focal accumulation of mutant Htt-positive foci, which occurred via an unknown mechanism. Conclusions: These data show that miR-22 has multipartite anti-neurodegenerative activities including the inhibition of apoptosis and the targeting of mRNAs implicated in the etiology of HD. These results motivate additional studies to evaluate the feasibility and therapeutic efficacy of manipulating miR-22 in vivo.

Public Library Science2013