Structural insights into the cytoplasmic domain of a human BK channel.
The large conductance, voltage- and Ca(2+) -activated K(+) (BK or Slo1) channel is widely expressed in mammalian cells/tissues (i.e. neurons, skeletal and smooth muscles, exocrine cells, the inner ear) and regulates action potential firing, muscle contraction and secretion. The large ionic conductance and unusual, dual stimulus-driven gating behavior of this channel have long intrigued membrane biophysicists, and recent structure/function analyses have provided increasingly detailed insights into the molecular "bells and whistles" that regulate BK channel activity. Now, in two complementary articles published by the groups of Rod MacKinnon and Youxing Jiang, high resolution x-ray crystal structures of the human BK channel's large cytoplasmic domain have been solved in both the absence and presence of bound Ca(2+), conditions which would presumably promote the resting and activated conformations of this large domain. Given the regulatory importance of the cytosolic domain on BK channel gating, these experimentally determined structures reveal a number of key insights, including: 1) the physical arrangement and interactions of the tandem RCK1 and RCK2 domains within a single channel subunit, 2) the assembly of the four large cytoplasmic domains into a symmetric, tetrameric complex, 3) the formation of the channel's "gating ring" structure, based on the assembly of the individual RCK1 and 2 domains, and 4) the structural elements underlying the regions critical for divalent metal ion binding (i.e. Ca (2+) and Mg (2+)) and their potential influence on conduction pore.
Department of Physiology and Pharmacology, University of Calgary, AB, Canada. abraun@ucalgary.ca
Andrew P
AP
Braun
D000200:Action Potentials; D002118:Calcium / Q000378:metabolism; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000737:chemistry* / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D008274:Magnesium; D002118:Calcium