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Phospho- and natural-variant regulation of heterotrimeric G protein signaling

Award Number: R35GM153492
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/06/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Phospho- and natural-variant regulation of heterotrimeric G protein signaling - Project Summary/Abstract Numerous cellular signaling pathways of critical importance to organism health rely on heterotrimeric G protein signaling. Heterotrimeric G proteins are composed of Gα, Gβ, and Gγ subunits. Classically, ligand binding to transmembrane G-protein-coupled-receptors (GPCRs) elicits conformational changes that lead to exchange of GDP for GTP on the Gα subunit, and resultant separation of Gα from the Gβγ dimer, either or both of which then signal to downstream effector proteins until intrinsic GTPase activity of Gα restores the heterotrimeric state. G proteins participate in numerous signaling cascades in both metazoan and plant systems and many aspects of G protein signaling are remarkably conserved across this evolutionary divide. The overarching goal of my research is to harness the simpler G protein complement of the model plant, Arabidopsis thaliana, to reveal how heterotrimeric G protein genotypes and molecular phenotypes control cellular signaling cascades, and thus whole organism consequences. Our laboratory has been a leader in plant heterotrimeric G protein signaling for >25 years; we have elucidated G protein signaling via methods ranging from single cell electrophysiology to imaging to -omics approaches, to sophisticated whole organism phenotyping and genome-phenome analyses. This proposal focuses on two types of molecular phenotypes – phosphorylation and natural variation -- and their attendant consequences on G protein biochemistry, cellular signaling, and whole organism vitality. We have ascertained that Gα phosphorylation at sites conserved across mammalian and plant Gαs can dramatically impact the G protein cycle. In Theme 1, we plan to utilize >60 Gα phosphomimic and phosphonull lines we have created to determine the phenotypic consequences of Gα phosphostatus. We will assess how phosphorylation changes Gα molecular partners (i.e. how phosphorylation biases signaling), and phenotypic consequences. We propose that phosphorylation “diversifies” the number of functionally distinct Gα proteins, resolving an apparent mismatch between the number of G protein subunits vs. the much greater numbers of GPCRs and phenotypes. Some G protein mutations are known to cause disease. Many more are statistically “associated’ with disease outcomes, but whether they actually cause disease is difficult to ascertain due to the high heterozygosity of humans, low phenotypic penetrance, and inaccessibility of humans to experimentation. Arabidopsis is naturally inbred and can be genetically manipulated with ease. In Theme 2 research, we plan to determine the impact of natural missense single nucleotide variants (SNVs) on Gα biochemistry. We will next experimentally reveal in Arabidopsis the phenotypic consequences of these mutations. Then we will ask whether, in nature, deleterious SNVs are accompanied by other SNVs in Gα that forestall the negative consequences of the missense mutations, in positive “intrageneic epistasis”. Next, we will assess intergenic epistasis between Gα variants and regulatory proteins. Demonstration of such phenomena is both mechanistically revealing and will allow medical science to better ascertain whether or not an individual with a given Gα SNV is actually predisposed to disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $396,275 )
2026	2026	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	3	2/20/2026	NON-COMPETING CONTINUATION	$396,275
														Subtotal = $396,275

Issue Date FY: 2025 ( Subtotal = $387,544 )
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	2	4/9/2025	NON-COMPETING CONTINUATION	$387,544
2025	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	11/27/2024	NEW	$0
														Subtotal = $387,544

Issue Date FY: 2024 ( Subtotal = $388,052 )
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	5/6/2024	NEW	$388,052
														Subtotal = $388,052

Grand Total All Awards = $1,171,871

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Phospho- and natural-variant regulation of heterotrimeric G protein signaling

Award Number: R35GM153492

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/06/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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