Structure and Dynamics of Macromolecular Complexes

From unicellular to multicellular organisms, a defining feature of life is that cells are bounded by a membrane formed by a lipid bilayer. Within the bilayer are so-called "integral" membrane proteins that mediate communication between the extracellular and intracellular environments. The membrane proteins fall into the general categories of transporters (e.g., for importing peptides as nutrients), channels (e.g., for mediating the flow of ions in and out of cells) and receptors (e.g., G Protein Coupled Receptors (GPCRs), to which ligands and hormones bind to regulate cellular metabolism. A major research theme in our laboratory is the determination of structures of such human proteins, which provide an essential foundation of knowledge for understanding normal physiology and mechanisms of disease. Our work is focused on 3 human membrane proteins with significant impact on human health and disease: Project (1): Connexin channels coordinate the electrical and metabolic activity of all tissues, exemplified by the heartbeat and ejection of blood from the ventricles, Project (2) The platelet integrin aIIbb3 mediates normal wound healing as well as clot formation during strokes and "heart attacks" (myocardial infarctions) and Project (3) Adenosine receptor A2a G- protein complexes participate in regulation of tissue inflammation. Project (1): Many pathophysiological states contribute to tissue injury, which is accompanied by elevation of cellular Ca2+ and acidic pH. Over the last decade we have discovered how Ca2+ ions and acidic pH block the channels to prevent permeation of K+ ions that can lead to arrhythmias and sudden death. Our current studies are examining how the lipids can interact with the channels to regulate activity. We are also examining mutations of connexin channels that can lead to diseases ranging from deafness to dermatologic conditions. Project (2) Activation of the platelet integrin aIIbb3 is critical for thrombus formation in normal wound healing and also stroke and myocardial infarction. We recently published the first high-resolution cryoEM structure of the full-length integrin in native membrane lipids. For the first time, the map revealed the individual transmembrane a-helices of the aIIb and b3 subunits, which are essential for signal transduction across the membrane resulting in platelet activation. We are now examining conformational changes that occur upon binding drugs that can be used to control clotting. Project (3): We recently solved the first high-resolution cryoEM structure of the native A2A adenosine receptor G-protein complex. A particular protein component (Gb4) exhibits a 10-fold increase in the efficiency for nucleotide exchange compared with Gb1. Our structure showed that the complex with Gb4 is more open to facilitate nucleotide exchange. We are now pursuing experiments to explore the idea that this open structure accounts for the 10-fold increase in efficiency. Ultimately, our studies will yield deeper insight into the structure and dynamics of three 3 physiologically and clinically important membrane proteins, Project Number: 1R35GM161827-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Mark Yeager | Institution: UNIVERSITY OF MIAMI CORAL GABLES, CORAL GABLES, FL | Award Amount: $501,165 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - E Study Section[MRAE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11260596