Abstract
The membrane attack complex (MAC) is a fundamental component of immune defence that drills holes in bacterial membranes and kill pathogens. MAC lesions were first identified in 1964, yet half a century later details of its structure and assembly mechanism remain undiscovered. Here we use electron cryo-microscopy to visualize the human pore complex at subnanometer resolution. We determine the protein composition of the MAC and identify interaction interfaces that hold the assembly together. Unlike closely related pore-forming proteins, the MAC’s asymmetric pore and “split-washer” shape suggest a killing mechanism that involves not only membrane rupture, but also distortion.
Bio
Doryen Bubeck received her PhD in Biophysics from Harvard University in 2005 where she used cryo-electron micrsocopy to investigate the cell entry mechanism of poliovirus. As an EMBO postdoctoral fellow and Cancer Research Institute Fellow at the University of Oxford, she continued to explore the structures of membrane proteins, focusing on the complement immune pathway. A recent highlight (Hadders & Bubeck et al., Cell Rep. 2012) is the discovery that complement components associate through a sideways alignment of their central MAC-perforin domains (MACPF). These results provide a structural framework for understanding the complex protein associations underlying activation of this innate immune effector. Doryen Bubeck is a lecturer in Structural Biology within the Department of Life Sciences and recipient of a Cancer Research UK Career Establishment Award. Her current research adopts an integrated structural approach merging cryo-electron microscopy and Xray crystallography to investigate the role of membrane proteins in host-pathogen interactions. She aims to investigate how membrane attack complex (MAC) pore formation is controlled, a process important for fighting infections and preventing complement-mediated tissue damage.