Potassium channel modulation by a toxin domain in matrix metalloprotease 23.
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.
Rangaraju
Srikant
S
Department of Physiology and Biophysics, University of California, Irvine, California 92697, USA.
Khoo
Keith K
KK
Feng
Zhi-Ping
ZP
Crossley
George
G
Nugent
Daniel
D
Khaytin
Ilya
I
Chi
Victor
V
Pham
Cory
C
Calabresi
Peter
P
Pennington
Michael W
MW
Norton
Raymond S
RS
Chandy
K George
KG
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003064:Cnidarian Venoms / Q000737:chemistry; D019143:Evolution, Molecular; D006801:Humans; D008666:Metalloendopeptidases / Q000737:chemistry*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010802:Phylogeny; D015221:Potassium Channels / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D012615:Sea Anemones / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D003064:Cnidarian Venoms; D010455:Peptides; D015221:Potassium Channels; C095391:ShK neurotoxin; C104455:toxin BgK; C492180:MMP23A protein, human; D008666:Metalloendopeptidases