TY - JOUR
T1 - Bilobal architecture is a requirement for calmodulin signaling to CaV1.3 channels
AU - Banerjee, Rahul
AU - Yoder, Jesse B.
AU - Yue, David T.
AU - Amzel, L. Mario
AU - Tomaselli, Gordon F.
AU - Gabelli, Sandra B.
AU - Ben-Johny, Manu
N1 - Publisher Copyright:
© 2018 National Academy of Sciences. All rights reserved.
PY - 2018/3/27
Y1 - 2018/3/27
N2 - Calmodulin (CaM) regulation of voltage-gated calcium (CaV) channels is a powerful Ca2+ feedback mechanism that adjusts Ca2+ influx, affording rich mechanistic insights into Ca2+ decoding. CaM possesses a dual-lobed architecture, a salient feature of the myriad Ca2+-sensing proteins, where two homologous lobes that recognize similar targets hint at redundant signaling mechanisms. Here, by tethering CaM lobes, we demonstrate that bilobal architecture is obligatory for signaling to CaV channels. With one lobe bound, CaV carboxy tail rearranges itself, resulting in a preinhibited configuration precluded from Ca2+ feedback. Reconstitution of two lobes, even as separate molecules, relieves preinhibition and restores Ca2+ feedback. CaV channels thus detect the coincident binding of two Ca2+-free lobes to promote channel opening, a molecular implementation of a logical NOR operation that processes spatiotemporal Ca2+ signals bifurcated by CaM lobes. Overall, a unified scheme of CaV channel regulation by CaM now emerges, and our findings highlight the versatility of CaM to perform exquisite Ca2+ computations.
AB - Calmodulin (CaM) regulation of voltage-gated calcium (CaV) channels is a powerful Ca2+ feedback mechanism that adjusts Ca2+ influx, affording rich mechanistic insights into Ca2+ decoding. CaM possesses a dual-lobed architecture, a salient feature of the myriad Ca2+-sensing proteins, where two homologous lobes that recognize similar targets hint at redundant signaling mechanisms. Here, by tethering CaM lobes, we demonstrate that bilobal architecture is obligatory for signaling to CaV channels. With one lobe bound, CaV carboxy tail rearranges itself, resulting in a preinhibited configuration precluded from Ca2+ feedback. Reconstitution of two lobes, even as separate molecules, relieves preinhibition and restores Ca2+ feedback. CaV channels thus detect the coincident binding of two Ca2+-free lobes to promote channel opening, a molecular implementation of a logical NOR operation that processes spatiotemporal Ca2+ signals bifurcated by CaM lobes. Overall, a unified scheme of CaV channel regulation by CaM now emerges, and our findings highlight the versatility of CaM to perform exquisite Ca2+ computations.
KW - Ca1.3
KW - Calcium regulation
KW - Calmodulin
KW - Ion channels
KW - Voltage-gated Ca channels
UR - http://www.scopus.com/inward/record.url?scp=85044517365&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044517365&partnerID=8YFLogxK
U2 - 10.1073/pnas.1716381115
DO - 10.1073/pnas.1716381115
M3 - Article
C2 - 29531055
AN - SCOPUS:85044517365
SN - 0027-8424
VL - 115
SP - E3026-E3035
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 13
ER -