Potassium Channel Modulation by a Toxin Domain in Matrix Metalloprotease 23

Rangaraju, S; Khoo, KK; Feng, ZP; Crossley, G; Nugent, D; Khaytin, I; Chi, V; Pham, C; Calabresi, P; Pennington, MW; Norton, RS; Chandy, KG

Author(s): Rangaraju, S; Khoo, KK; Feng, ZP; Crossley, G; Nugent, D; Khaytin, I; Chi, V; Pham, C; Calabresi, P; Pennington, MW; Norton, RS; Chandy, KG;
Details: Publication Year 2010-03-19,Volume 285,Issue #12,Page 9124-9136
Journal Title: JOURNAL OF BIOLOGICAL CHEMISTRY
Publication Type: Journal Article
Abstract: Peptide toxins found in a wide array of venoms block K(+) channels, causing profound physiological and pathological effects. Here we describe the first functional K(+) channel-blocking toxin domain in a mammalian protein. MMP23 (matrix metalloprotease 23) contains a domain (MMP23(TxD)) that is evolutionarily related to peptide toxins from sea anemones. MMP23(TxD) shows close structural similarity to the sea anemone toxins BgK and ShK. Moreover, this domain blocks K(+) channels in the nanomolar to low micromolar range (Kv1.6 > Kv1.3 > Kv1.1 = Kv3.2 > Kv1.4, in decreasing order of potency) while sparing other K(+) channels (Kv1.2, Kv1.5, Kv1.7, and KCa3.1). Full-length MMP23 suppresses K(+) channels by co-localizing with and trapping MMP23(TxD)-sensitive channels in the ER. Our results provide clues to the structure and function of the vast family of proteins that contain domains related to sea anemone toxins. Evolutionary pressure to maintain a channel-modulatory function may contribute to the conservation of this domain throughout the plant and animal kingdoms.
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords: RICH SECRETORY PROTEIN; NICOTINIC ACETYLCHOLINE-RECEPTORS; GENE-EXPRESSION PROFILE; CRYSTAL-STRUCTURE; SNAKE-VENOM; SEA-ANEMONE; NMR-SPECTROSCOPY; ION CHANNELS; K+ CHANNEL; SHK TOXIN
Publisher's Version: https://doi.org/10.1074/jbc.M109.071266
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2010-03-19 12:00:00