Intracellular Trafficking of the KV1.3 Potassium Channel Is Regulated by the Prodomain of a Matrix Metalloprotease

Matrix metalloproteases (MMPs) are endopeptidases that regulate diverse biological processes. Synthesized as zymogens, MMPs become active after removal of their prodomains. Much is known about the metalloprotease activity of these enzymes, but noncanonical functions are poorly defined, and functions of the prodomains have been largely ignored. Here we report a novel metalloprotease-independent, channel-modulating function for the prodomain of MMP23 (MMP23-PD). Whole-cell patch clamping and confocal microscopy, coupled with deletion analysis, demonstrate that MMP23-PD suppresses the voltage-gated potassium channel K_V1.3, but not the closely related K_V1.2 channel, by trapping the channel intracellularly. Studies with K_V1.2-1.3 chimeras suggest that MMP23-PD requires the presence of the K_V1.3 region from the S5 trans-membrane segment to the C terminus to modulate K_V1.3 channel function. NMR studies of MMP23-PD reveal a single, kinked trans-membrane α-helix, joined by a short linker to a juxtamembrane α-helix, which is associated with the surface of the membrane and protected from exchange with the solvent. The topological similarity of MMP23-PD to KCNE1, KCNE2, and KCNE4 proteins that trap K_V1.3, K_V1.4, K_V3.3, and K_V3.4 channels early in the secretory pathway suggests a shared mechanism of channel regulation. MMP23 and K_V1.3 expression is enhanced and overlapping in colorectal cancers where the interaction of the two proteins could affect cell function.