ad hoc ORNN seminar: A/Prof. Carsten Mim 'From Structure to Pathophysiology: Using Cryo-EM to Resolve Functional Protein States'


Please join us in person CHG Seminar Room B - 12:00 - 13:00 or online https://teams.microsoft.com/l/meetup-join/19%3ameeting_YzZkYmExODItMTBmMi00YmFhLWEzNTktYmY0NjM0OGQwNDU2%40thread.v2/0?context=%7b%22Tid%22%3a%22cc95de1b-97f5-4f93-b4ba-fe68b852cf91%22%2c%22Oid%22%3a%220e65676c-585d-4752-9c38-ca6aa1c3b69b%22%7d

Electron microscopy (cryo-EM) is an essential tool to visualize proteins in near-native conditions. This is particularly true when dealing with heterogeneity—a hallmark of biological systems in health and disease. I will discuss how cryo-EM can uncover clinically relevant structural states using the membrane channel Pannexin-1 (PANX1) as a case study. PANX1 plays key roles in inflammation, ischemic injury, and immune cell activation due to its central role in ATP release. Yet, its regulation of the ATP-release state remains poorly understood. Using cryo-EM, we separated two PANX1 conformations and identified how phosphorylation stabilizes the open, large-pore state, enabling the passage of ATP and metabolites. This provides a structural basis for PANX1 activation in inflammatory and disease contexts. In a second example, cryo-EM allowed us to resolve compositional heterogeneity in a mixed protein sample, identifying three distinct structures—including one previously uncharacterized complex—at better than 3.5 Å. Together, these studies highlight cryo-EM’s power in deciphering biologically and clinically important complexity.