Ecosystem
Beta Site
Session I
Tethered agonist-dependent/independent activation mechanism in AGPCRs
Signaling Properties of ADGRL3
Signe Mathiasen
Abstract
Only available for AGPCR 24 Workshop Attendees
Authors & Affiliations
"Rosell, Júlia (1) Holmkvist, Jesper L. (1) Arastoo, Mohammad Reza (1) Vejre, Phillip C. (1) Regmi, Rajesh (1) Perry-Hauser, Nicole A. (2) Bendix, Poul Martin (3) Javitch, Jonathan A. (2) Mathiasen, Signe (1)
1. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
2. Departments of Psychiatry and Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA
3. Niels Bohr Institute, Faculty of Natural Sciences, University of Copenhagen, Copenhagen, Denmark"
About Signe Mathiasen
"2022-present
Assistant Professor (Tenure Track) and Group Leader
Department of Biomedical Sciences, University of Copenhagen.
2020 – 2022: Assistant Professor
Department of Biomedical Sciences, University of Copenhagen.
2014-2021:
Postdoc / Assistant Professor
Department of Psychiatry, Columbia University, New York, USA.
New York State Psychiatric Institute, Research Foundation for Mental Hygiene, New York, USA.
Postdoc Supervisor Professor Jonathan Javitch
2013:
PhD in Nanoscience/Biophysics. Department of Chemistry, University of Copenhagen, Copenhagen Denmark.
PhD Supervisor Professor Dimitrios Stamou."
Signe Mathiasen on the web
An ECR-Mediated and TA-independent Mechanism of aGPCR Activation: Direct Communication of Extracellular Region with Transmembrane Domain in a Holo-Adhesion GPCR
Demet Araç
Abstract
"According to the Tethered Agonist (TA)-mediated model of aGPCR activation, the ECR acts as a protective cap for the TA peptide to hide it within the GAIN domain. However, several recent observations suggest that other mechanisms of aGPCR activation are possible. For example, some aGPCRs do not undergo autoproteolysis, which is required for TA release. Even the aGPCRs that are cleaved do not always require cleavage for mediating some aspects of wild type functions. It has been suggested that the TA can regulate receptor signaling without coming out of the GAIN domain or by being partially exposed, however the recent TA-bound 7TM structures of multiple aGPCRs showed that the critical phenylalanine residue and other important TA residues have to reach deep into the 7TM orthosteric pocket for receptor activation, suggesting that non-release or partial release of the TA is unlikely to activate the receptor. In this talk, I summarize accumulating data from our lab and the aGPCR field that suggests an additional model in which the conformation of the Extracellular Region (ECR) has a direct role in modulating the 7TM signaling, independently of TA-mediated activation.
Our results provide evidence for the ECR-mediated activation of aGPCR as a complementary mechanism for the TA-mediated activation of aGPCRs. Many biological forces are smaller than 200 pN, the force that is needed to separate the TA from the GAIN domain. To sense these smaller forces, and to regulate aGPCR function on and off, a mechanism that does not depend on ECR dissociation and TA exposure might be at work. At low force or no force conditions, aGPCR may be reversibly regulated by binding and dissociation of a ligand to the ECR without ECR shedding and TA exposure. In this ECR-mediated mechanism of activation, the ECR-7TM communication is altered by transient interactions between ECR and 7TM. The TA peptide remains at its original position and is not involved in signaling. Because the TA-mediated mechanism is a “one and done” mechanism that is irreversible and prevents the receptor from going back to its inactive resting state, the ECR-mediated mechanism may operate in situations where a reversible regulation is needed. The ECR-mediated mechanism may also enable responding to compressing forces on the receptor, that directly “push” on the protein. In cases where a large “pulling” force is executed on the ECR, the ECR may be removed from the 7TM releasing the tethered agonist and activating the aGPCR irreversibly but acutely. ECR-mediated mechanism opens new possibilities for drugging aGPCRs. Future work that dissects different activation mechanisms of aGPCRs in different physiological contexts will shed light on this fascinating family of receptors. "
Authors & Affiliations
"Kordon Szymon P.1, 2, Cechova Kristina3, Bandekar Sumit J.1, 2, Ethan Dintzner1, 2, Leon Katherine1, 2, Dutka Przemysław1, Siffer Gracie3, Kossiakoff Anthony A.1, Sando Richard 4, Vafabakhsh Reza3, Araç Demet1, 2
1. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago; 2. Neuroscience Institute, Institute for Biophysical Dynamics, and Center for Mechanical Excitability, The University of Chicago, 3. Department of Molecular Biosciences, Northwestern University; 4. Vanderbilt University"
About Demet Araç
"Demet was an undergraduate at Bilkent University in Turkey, where she majored in Molecular Biology and Genetics. She moved to the University of Texas Southwestern Medical Center at Dallas in 2000 to work with Dr. Jose Rizo-Rey as a graduate student to elucidate the mechanisms of neurotransmitter release. After finishing her graduate training, she joined Dr. Axel Brunger’s lab at Stanford University to study the structure and function of cell-adhesion proteins at the synapse. In 2013, Demet began her independent research career at the University of Chicago within the Department of Biochemistry and Molecular Biology."
Demet Araç on the web
Structural Insights into the Activation Mechanisms of Adhesion GPCRs
Yan Zhang
Abstract
"Adhesion G protein-coupled receptors (aGPCRs) represent a relatively understudied class of GPCRs, yet they are implicated in various physiological and pathological processes. A comprehensive understanding of their signaling mechanisms is essential for the development of modulators for diseases such as cancer, immune disorders, and neurological conditions. In our previous work, we reported the structures of a prototypical aGPCR CD97 in both inactive and active states, revealing a compact inactive conformation and significant conformational changes upon activation, particularly on the intracellular and extracellular sides. We also identified key motifs involved in aGPCR activation. Recently, we have elucidated the high-resolution structures of GPR97 transitioning from its inactive state to both G protein-coupled and arrestin-coupled states. Our findings highlight pronounced conformational shifts across the receptor, especially involving transmembrane helices TM5 and TM6. Notably, we discovered that activation by small molecule ligands and peptide tethered ligands induces markedly different mechanisms of ligand recognition, activation, and coupling, resulting in differential signaling pathways. These insights contribute to a deeper understanding of the signaling mechanisms of aGPCRs, which could inform future therapeutic strategies."
Authors & Affiliations
"Chunyou Mao, Zhejiang University"
About Yan Zhang
"Zhang Yan, Changjiang Scholar of the Ministry of Education, Qiushi Distinguished Professor, Deputy Dean of the School of Basic Medicine, Deputy Director of the Center for Innovative Drug Research, Zhejiang University, Director of Cryo-electron Microscopy Center of Liangzhu Laboratory, Winner of Tan Jiazhen Life Innovation Award and Shulan Medical Youth Award."
Yan Zhang on the web
Heterogeneity of Tethered Agonist Signaling in Adhesion G Protein-Coupled Receptors
Andrew Dates
Abstract
Only available for AGPCR 24 Workshop Attendees
Authors & Affiliations
"Daniel T.D. Jones (Harvard Medical School); Jeffrey S. Smith (Harvard Medical School, Brigham and Women's Hospital); Meredith A. Skiba (Harvard Medical School); Maria F. Rich (University of Cincinnati School of Medicine); Maggie M. Burruss (Harvard Medical School); Andrew Kruse (Harvard Medical School); Stephen C. Blacklow (Harvard Medical School)"
About Andrew Dates
"Drew Dates received his B.S. in Biological Chemistry from Carnegie Mellon University in 2018. As an undergraduate, he studied opioid receptor trafficking and G protein conformational dynamics in the laboratories of Manojkumar Puthenveedu and Roger Sunahara, respectively. As part of his doctoral work in the Blacklow laboratory at Harvard Medical School, Drew studied structure-function relationships in the Adhesion Family of GPCRs."
Andrew Dates on the web
Discriminating between the extracellular scaffolding and G protein signaling roles of GPR56/ADGRG1 via the characterization of a non-cleavable point mutant knock-in mouse, H381S
Frank Kwarcinski
Abstract
Only available for AGPCR 24 Workshop Attendees
Authors & Affiliations
""Tyler F. Bernadyn, Mariane Nascimento, Xinyi Lu, Pauline L. Pan, Michael Holinstat and Gregory G. Tall
Department of Pharmacology, University of Michigan ""
About Frank Kwarcinski
"I am research faculty within the department of Pharmacology at the University of Michigan. I work under the supervision of Dr. Gregory Tall and our research primarily focuses on the structural and biochemical characterization of adhesion GPCRs (AGPCR) for mechanism of action and pathogenesis studies. We utilize several genetically modified mouse models to investigate requirements for receptor activator and continuously work to identify novel chemical modulators of AGPCRs through assay development and high-throughput screening efforts. I have previous work experience at two separate contract research organizations centered on assay development, and I am formally trained as a chemical biologist."
Frank Kwarcinski on the web
Tethered Peptide Activation Mechanism of Adhesion GPCRs
Peng Xiao
Abstract
Only available for AGPCR 24 Workshop Attendees
About Peng Xiao
"I joined Prof. Jin-Peng Sun’s Lab since I graduated from Shandong University in 2012, and worked under the guidance of Prof. Sun as a postdoc/research associate/assistant professor. Since then, I have been working on dissecting the three-dimensional architecture and underlying molecular signaling mechanism of GPCR using cryo-electron microscopy (cryo-EM). So far, I have published 20 peer-reviewed papers as correspondence (or co- correspondence) or first (or co-first) authors, among which, four papers were published in Nature (2022a, 2022b, 2021, 2020); one paper was published in Cell (2021); on paper was published in Science (2023); two papers were published in Nat Chem Biol. (2022, 2018)."