Intracellular trafficking of the KV1.3 potassium channel is regulated by the prodomain of a matrix metalloprotease

Hai M Nguyen, Charles Galea, Galina Schmunk, Brian J Smith, Robert A Edwards, Raymond Stanley Norton, K George Chandy

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22 Citations (Scopus)


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(V)1.3, but not the closely related K(V)1.2 channel, by trapping the channel intracellularly. Studies with K(V)1.2-1.3 chimeras suggest that MMP23-PD requires the presence of the K(V)1.3 region from the S5 trans-membrane segment to the C terminus to modulate K(V)1.3 channel function. NMR studies of MMP23-PD reveal a single, kinked trans-membrane alpha-helix, joined by a short linker to a juxtamembrane alpha-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(V)1.3, K(V)1.4, K(V)3.3, and K(V)3.4 channels early in the secretory pathway suggests a shared mechanism of channel regulation. MMP23 and K(V)1.3 expression is enhanced and overlap-ping in colorectal cancers where the interaction of the two proteins could affect cell function.
Original languageEnglish
Pages (from-to)6451 - 6464
Number of pages14
JournalJournal of Biological Chemistry
Issue number9
Publication statusPublished - 2013

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