The Annexin V Transmembrane Channel

Abstract

Annexins are a family of proteins that bind calcium. Upon calcium binding, annexins have high affinity for anionic phospholipids and bind to the plasma membrane. They have been implicated in several cell biological processes including membrane stabilization and repair, and endocytosis and exocytosis. Annexins are also found in the extracellular space and have been shown to be involved in coagulation and apoptosis. In the 1990s, based on functional measurements, annexins have also been evidenced to form calcium ion channels. However, the more than 80 annexin structures solved, all revealed a soluble protein, and the ion channel function remained an unexplained oddity. Here, we report the direct monitoring of annexin-V (A5) interactions with membranes in real time and native-like environments using high-speed atomic force microscopy (HS-AFM) imaging. We provide first compelling evidence of a transmembrane annexin ion channel structure that is composed of a central pore-forming trimer surrounded by a hexamer-of-A5-trimers. Our findings revive the proposal that Annexin can adopt a so far never observed transmembrane state and A5's multiple functions in and outside cells.