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. Matrix metalloprotease 23 (MMP23) 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, and the 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, KCa3.1). Full-length MMP23 suppresses K+ channels with a pattern of inhibition consistent with MMP23TxD activity. 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 kingdom.
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