Voltage-gated potassium (Kv) channels play a fundamental role in biology and disease and are regulated by mechanisms that control the flow of ions and the number of channels at the cell surface. We have recently identified a novel mechanism regulating the trafficking of Kv channels that is mediated by the matrix metalloprotease MMP23.(1, 2)
Matrix metalloproteases (MMPs) are a family of endopeptidases possessing a common domain architecture: a folded N-terminal auto-inhibitory pro-domain, a central protease domain and a C-terminal hemopexin domain. In contrast, the pro-domain of MMP23 (MMP23-PD) is largely unstructured and contains a transmembrane domain (TMD) that anchors the protein to the plasma membrane while the hemopexin domain is replaced by a toxin-like domain (TxD) and an immunoglobulin-like cell adhesion molecule (IgCAM) domain. The TxD shares sequence homology with several sea anemone toxins that are known to block Kv channels. We show the TxD has a structure and Kv channel blocking activity similar to these toxins.
More recently we reported a novel channel-modulating function for MMP23-PD. MMP23-PD suppresses Kv1.3, but not closely related Kv1.2 channel activity, by trapping them intracellularly. Kv1.2-Kv1.3 chimeras show that MMP23-PD’s modulatory role requires the pore domain (S5-P-S6) of Kv1.3. NMR studies reveal that MMP23-PD contains a single transmembrane -helix joined by a short linker to an -helix that is associated with the membrane surface. Immunohistochemistry shows MMP23 and Kv1.3 have similar staining patterns in human colonic epithelium, where the two proteins may interact, and both are over-expressed in human colorectal cancers. Overall, our data suggest that MMP23 regulates the intracellular trafficking of Kv1.3 potassium channels via an interaction of MMP23-PD with the Kv1.3 pore domain. This represents a unique form of regulation that will significantly add to our understanding of mechanisms controlling Kv channel trafficking and targeting in cells.