title: Intracellular trafficking of the KV1.3 potassium channel is regulated by the prodomain of a matrix metalloprotease.
abstract: 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 KV1.3, but not the closely related KV1.2 channel, by trapping the channel intracellularly. Studies with KV1.2-1.3 chimeras suggest that MMP23-PD requires the presence of the KV1.3 region from the S5 trans-membrane segment to the C terminus to modulate KV1.3 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 KV1.3, KV1.4, KV3.3, and KV3.4 channels early in the secretory pathway suggests a shared mechanism of channel regulation. MMP23 and KV1.3 expression is enhanced and overlapping in colorectal cancers where the interaction of the two proteins could affect cell function.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California92697, USA.
authors.forename: Hai M
authors.initials: HM
authors.lastname: Nguyen
authors.forename: Charles A
authors.initials: CA
authors.lastname: Galea
authors.forename: Galina
authors.initials: G
authors.lastname: Schmunk
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Robert A
authors.initials: RA
authors.lastname: Edwards
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.forename: K George
authors.initials: KG
authors.lastname: Chandy
mesh_terms: D000818:Animals; D019556:COS Cells; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D051663:Kv1.2 Potassium Channel / Q000235:genetics / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology
chemical_list: D051663:Kv1.2 Potassium Channel; D051664:Kv1.3 Potassium Channel; D009363:Neoplasm Proteins; C492180:MMP23A protein, human; D008666:Metalloendopeptidases