Potassium channel modulation by a toxin domain in matrix metalloprotease 23

Srikant Rangaraju, Keith K. Khoo, Zhi Ping Feng, George Crossley, Daniel Nugent, Ilya Khaytin, Victor Chi, Cory Pham, Peter Calabresi, Michael W. Pennington, Raymond S. Norton, K. George Chandy

Research output: Contribution to journalArticlepeer-review

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 (MMP23TxD) that is evolutionarily related to peptide toxins from sea anemones. MMP23TxD 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.

Original languageEnglish (US)
Pages (from-to)9124-9136
Number of pages13
JournalJournal of Biological Chemistry
Volume285
Issue number12
DOIs
StatePublished - Mar 19 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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