Structures of a calcium channel reveal crosstalk of intracellular segments

What is it about?

This study reports the high-resolution cryo-electron microscopy structure of human Cav2.3 in complex with two of its subunits at an overall resolution of 3.1 Å. The structure is nearly identical to that of Cav2.2, with a crucial voltage-sensing domain (VSDII) in the down state (deeply buried inside the membrane) and the other three VSDs up. A lipid membrane based molecule (PIP2) binds to the interface of VSDII and the tightly closed pore domain. We also determined the cryo-EM structure of a mutated Cav2.3 channel in which a Cav2-unique intracellular helix (designated the CH2II helix) is deleted. This mutant, named ΔCH2, still reserves a down VSDII, but PIP2 is invisible and the region on the intracellular side close to the membrane is barely visible. Our structural and electrophysiological characterizations of the wild type and mutated ΔCH2 Cav2.3 show that the CH2II helix stabilizes the inactivated (closed) conformation of the channel by tightening the intracellular segments close to the membrane, while CH2II helix is not necessary for locking the down state of VSDII.

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Why is it important?

This calcium channel is very imporatant for signalling of nerve cells and plays an important role in several diseases. Knowing the detailed nearly atomic resolution structure of this protein will allow rational design of new drugs and molecules to manipulate this channel to treat such diseases but it also helps us to better understand how these proteins function and/or malfunction in specific diseases and to better understand nerve signalling in general.