# Investigation of Adhesion GPCR and Ric-8 protein control of heterotrimeric G proteins

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $609,617

## Abstract

Project Summary: This MIRA proposal will combine work from our longstanding projects on the structure and
function of adhesion G protein coupled receptors (or Family B2 GPCRs) and the molecular chaperones for G
protein alpha subunits, Ric-8 proteins. Adhesion GPCRs are a large, 33-member family of receptors that
transduce signals from cell to cell or cell to extracellular matrix adhesion events across the cell membrane to
awaiting G proteins in order to elicit responses within the cell. Our work has advanced a mechanism for adhesion
GPCR activation in which the extracellular adhesion domains become anchored to protein ligands and the cell
that contains the GPCR or seven transmembrane domain (7TM) moves, by any number of means, in relation to
this fixed anchor to dissociate the two halves of the adhesion GPCR. This dissociation event reveals a previously
hidden tethered agonist of the GPCR/7TM domain that self-activates the receptor. This mode of activation
seems common to most members of the adhesion GPCR family, but alternative modes of adhesion GPCR
activation have also come to the fore of the field. Our goal in this proposal is to expand upon our mechanistic
and structural work to decipher varied adhesion GPCR activation modes using biochemical, cell biological, and
in vivo approaches, including work with two mouse models newly created for this proposal. We will focus on
adhesion GPCRs that are present in cells that circulate in the blood, for example ADGRG1/GPR56 on platelets,
as well as additional ADGRG subfamily members present on other circulating cell types. Circulating cells offer
an advantage for interrogating adhesion GPCR action because the shear force component that dissociates the
two fragments of the receptors, for the purpose of tethered-agonist-activation, is readily tractable. The sum of
our work will be to distinguish tethered agonist -dependent and -independent modes of adhesion GPCR
activation, which we argue is perhaps the most important contemporary question in the adhesion GPCR field.
In parallel, we have assigned the function of Ric-8A and Ric-8B proteins as molecular chaperones that are
required to collectively fold all G protein alpha subunits. This is a mature project for our lab, yet we have made
recent breakthroughs in solving the structures of Ric-8/G protein guanine nucleotide-free complexes. We
present preliminary evidence of a new Ric-8/G protein complex structure that will enable us to finally tackle a
major outstanding question; What are the structural elements of mammalian Ric-8A and Ric-8B that define their
specificities for different G protein subtypes? Combined with analysis of the single copy of an ancestral Ric-8
(Drosophila Ric-8) that seemingly crosses the lines and appears to fold all G protein subtypes, our work will
provide new understanding of the substrate specificity rules, thereby providing a rationale for potentially targeting
the Ric-8 chaperone system in contexts of G protein-driven disease.

## Key facts

- **NIH application ID:** 10804700
- **Project number:** 5R35GM149539-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Gregory Gordon Tall
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $609,617
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804700

## Citation

> US National Institutes of Health, RePORTER application 10804700, Investigation of Adhesion GPCR and Ric-8 protein control of heterotrimeric G proteins (5R35GM149539-02). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10804700. Licensed CC0.

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