connexin-26 gap junction channel
Human (Homo sapiens)
The body of higher animals like human is composed of a huge number of cells and the intercellular communication is critically important for their biological activities. There are several means in the intercellular signaling, such as secreted molecules like hormone or neurotransmitter and its receptor, and adhesive molecules like cadherin or integrin. They areall mediated through membrane proteins. On the other hand, the gap junction is specialized membrane region where intercellular connecting channels called gap junction channels cluster. It is essential for the synchronous contraction of cardiomyocytes in hearts and keeping homeostasis for transparency in lens. A number of mutations in connexin genes, which encode transmembrane protein constituting gap junction channels, are associated with various human diseases.
In spite of the intensive structural studies by electron microscopy (EM) since its first finding, the structural detail of the gap junction channel has long been unknown, such as helical arrangement or the docking interactions. We have recently determined the atomic structure of human connexin26 (Cx26) gap junction channel by X-ray crystallography. The structure reveals the atomic basis for the organization and suggests the gating mechanism of it.
The observed channel is in the head-to-head docked state that spans two plasma membranes as an intercellular channel. The overall appearance is like that of tsuzumi, a traditional Japanese drum (Figure1).
There is a central channel path along with the long axis of it, whose diameter is about 1.4nm at the narrowest point. The crystallographic analysis clearly shows the pore-lining residues, which will promote the functional studies on the different molecular permeability that each connexin has (Figure2).
The observed structure is in the open conformation. Recently, low resolution EM analysis has shown it in its closed conformation. The EM map shows a large electron density (plug) on the top of the pore, which is supposed to close the pore physically. In the X-ray atomic structure, there are six N-terminal helices forming a molecular funnel (Figure3).
The previous studies suggested that the N-terminal region functions as a sensor for the trans-junctional voltage difference. Based on the functional studies and the two structures, we have proposed a model that the funnel undergoes conformational change and forms a plug to close the pore.
Protein Data Bank (PDB)
author: Shoji Maeda