Functional modularity of the beta-subunit of voltage-gated Ca2+ channels.
The beta-subunit of voltage-gated Ca(2+) channels plays a dual role in chaperoning the channels to the plasma membrane and modulating their gating. It contains five distinct modular domains/regions, including the variable N- and C-terminus, a conserved Src homology 3 (SH3) domain, a conserved guanylate kinase (GK) domain, and a connecting variable and flexible HOOK region. Recent crystallographic studies revealed a highly conserved interaction between the GK domain and alpha interaction domain (AID), the high-affinity binding site in the pore-forming alpha(1) subunit. Here we show that the AID-GK domain interaction is necessary for beta-subunit-stimulated Ca(2+) channel surface expression and that the GK domain alone can carry out this function. We also examined the role of each region of all four beta-subunit subfamilies in modulating P/Q-type Ca(2+) channel gating and demonstrate that the beta-subunit functions modularly. Our results support a model that the conserved AID-GK domain interaction anchors the beta-subunit to the alpha(1) subunit, enabling alpha(1)-beta pair-specific low-affinity interactions involving the N-terminus and the HOOK region, which confer on each of the four beta-subunit subfamilies its distinctive modulatory properties.
He
Lin-Ling
LL
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Zhang
Yun
Y
Chen
Yu-Hang
YH
Yamada
Yoichi
Y
Yang
Jian
J
D000818:Animals; D001921:Brain / Q000502:physiology; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D018360:Crystallography, X-Ray; D005260:Female; D009865:Oocytes / Q000502:physiology; D010053:Ovary / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011817:Rabbits; D017384:Sequence Deletion; D014162:Transfection; D018909:src Homology Domains
D015220:Calcium Channels; D021122:Protein Subunits