Strategic Partner(s)

Randy Hall: Adhesion GPCRs and the Tail Nobody Wanted

SCIENTIFIC ABSTRACT

Most of what the field now takes for granted about the C terminus of a GPCR was, in the mid 1990s, considered uninteresting. Randy Hall arrived in Bob Lefkowitz's lab from a background in ionotropic glutamate receptors, noticed that the beta adrenergic receptors carried short motifs resembling the ones that recruit scaffold proteins to NMDA receptors, and asked what bound there. He was told the answer was nothing. At the time, the lab chasing the first GPCR crystal structure was cutting the tail off entirely.

What he found reframed how the field explains why closely related receptor subtypes produce different effects on cell physiology.

This conversation follows that thread into adhesion GPCRs, a subfamily of 33 human receptors with enormous extracellular N termini that cleave themselves and then stay together. Hall describes the experiment designed to kill receptor signaling that instead amplified it, the tethered agonist model his lab proposed in 2011, and why a family once dismissed as undruggable now looks like a serious therapeutic frontier. He also explains how he came to write the memoir of his mentor, a project he pitched three times over fifteen years before the answer was yes.

ABOUT RANDY

Randy Hall is Professor of Pharmacology and Chemical Biology at Emory University School of Medicine, where he has run his lab since 1999. He trained with Gary Lynch at UC Irvine on ionotropic glutamate receptors, then with Thomas Soderling at the Vollum Institute on receptor trafficking and phosphorylation, before joining Bob Lefkowitz's lab at Duke to work on adrenergic receptor regulation.

His lab uses proteomic and interaction screening approaches to map the proteins that bind GPCR intracellular tails, and has published on receptors from the adrenergic, purinergic, glutamatergic, GABAergic and adhesion subfamilies. Recent work centers on GPR37 and GPR37L1 and on the adhesion receptors BAI1, BAI2 and GPR56, with a particular focus on disease associated mutations that disturb receptor signaling or trafficking. He is a Fellow of the AAAS and coauthor, with Bob Lefkowitz, of the 2021 memoir A Funny Thing Happened on the Way to Stockholm.

SCIENTIFIC THEMES OF THE CONVERSATION

- Why the GPCR C terminus turned out to determine subtype specific function

- Adhesion GPCRs: self cleaving receptors, huge N termini, and the tethered agonist model

- Constitutive activity as a disease mechanism, from the alpha 1 receptor to BAI2

- Orphan receptors and where the next generation of GPCR drugs will come from

- In silico screening, and what human plus machine collaboration means for drug discovery

- Problem selection: how young scientists choose what to spend years on

- Writing a scientific memoir, and why honesty is the load bearing part

KEY INSIGHTS FROM THE CONVERSATION

Changing subfields is when discovery happens

Hall deliberately chose a second postdoc in a different receptor family rather than extending his graduate work. He argues that staying close to a hot topic feels safe but narrows a scientist's development, and that the moment you carry one field's questions into another is often the most productive window of a career. His own case is the evidence: NMDA receptor scaffolding logic applied to beta adrenergic receptors.

The tail everyone was discarding

When Hall asked what the C termini of the beta adrenergic receptors did, the lab's answer was that they could be removed with G protein coupling intact. The structural effort underway at the time simply deleted them. That consensus is precisely why he went looking, and the distinct binding partners he found for beta 1 and beta 2 offered an explanation for how two subtypes coupling to the same G protein can have opposite effects on cell physiology.

Skepticism first, then a crowded field

The early data drew hard questions at Gordon conferences from senior figures who were not convinced. Within a few years, dozens of labs were running similar studies across every GPCR subfamily. Hall describes the real measure of acceptance as the moment other groups start doing the experiments themselves.

The experiment that did the opposite

Predicting that an endogenous ligand acted on the large N terminus of GPR56, his lab truncated it, expecting a dead receptor. Signaling increased massively instead, and the same held for BAI1. That inversion became the basis for the model his lab proposed in 2011, in which removing or reconfiguring the N terminus unveils a cryptic tethered agonist, and it has since been reproduced across the family by other groups.

From undruggable to promising

Drug development veterans long treated large adhesive proteins as poor targets because their interaction interfaces are too big to disrupt with small molecules. Hall's counterpoint is that adhesion GPCRs are not only adhesive proteins, they are also GPCRs, with a seven transmembrane pocket. Screening work has since produced agonists and antagonists, and the first cryo EM structure of an adhesion GPCR, GPR97, showed glucocorticoid binding, raising the possibility that steroid activation of G protein pathways has been hiding in this family.

When receptors are tuned and mutations detune them

The BAI2 mutation Hall's lab linked to a neurodegenerative condition sits on the C terminus and makes the receptor constitutively overactive, pointing back to the protein interactions he has studied since the 1990s. He traces the concept to basic work by Susanna Cotecchia on the alpha 1 receptor in the early 1990s, research with no clinical intent that became the template for explaining a long list of human diseases.

Choose important problems, not easy ones

Hall's advice to junior scientists is that trivial questions are not measurably easier to solve than important ones, so the years spent are better invested in something that matters. He recommends heading for subfields in turmoil, where there is disagreement and unsolved mystery, with the single constraint that the technology to answer the question must already exist.