TY - JOUR
T1 - Allosteric coupling between Mn2+and dsDNA controls the catalytic efficiency and fidelity of cGAS
AU - Hooy, Richard M.
AU - Massaccesi, Guido
AU - Rousseau, Kimberly E.
AU - Chattergoon, Michael A.
AU - Sohn, Jungsan
N1 - Funding Information:
American Cancer Society [DMC-RG-15-224]; National Institutes of Health (NIH) [GM129342A1 to J..S.]; NIH [AI102696 to M.A.C.]; Johns Hopkins School of Medicine Synergy Award (to J.S. and M.A.C.). Funding for open access charge: NIH.
Publisher Copyright:
© The Author(s) 2020.
PY - 2021
Y1 - 2021
N2 - Cyclic-G/AMP (cGAMP) synthase (cGAS) triggers host innate immune responses against cytosolic double-stranded (ds)DNA arising from genotoxic stress and pathogen invasion. The canonical activation mechanism of cGAS entails dsDNA-binding and dimerization. Here, we report an unexpected activation mechanism of cGAS in which Mn2+ activates monomeric cGAS without dsDNA. Importantly, the Mn2+-mediated activation positively couples with dsDNA-dependent activation in a concerted manner. Moreover, the positive coupling between Mn2+ and dsDNA length-dependent activation requires the cognate ATP/GTP substrate pair, while negativecooperativity suppresses Mn2+ utilization by either ATP or GTP alone. Additionally, while Mn2+ accelerates the overall catalytic activity, dsDNA lengthdependent dimerization specifically accelerates the cyclization of cGAMP. Together, we demonstrate how the intrinsic allostery of cGAS efficiently yet precisely tunes its activity.
AB - Cyclic-G/AMP (cGAMP) synthase (cGAS) triggers host innate immune responses against cytosolic double-stranded (ds)DNA arising from genotoxic stress and pathogen invasion. The canonical activation mechanism of cGAS entails dsDNA-binding and dimerization. Here, we report an unexpected activation mechanism of cGAS in which Mn2+ activates monomeric cGAS without dsDNA. Importantly, the Mn2+-mediated activation positively couples with dsDNA-dependent activation in a concerted manner. Moreover, the positive coupling between Mn2+ and dsDNA length-dependent activation requires the cognate ATP/GTP substrate pair, while negativecooperativity suppresses Mn2+ utilization by either ATP or GTP alone. Additionally, while Mn2+ accelerates the overall catalytic activity, dsDNA lengthdependent dimerization specifically accelerates the cyclization of cGAMP. Together, we demonstrate how the intrinsic allostery of cGAS efficiently yet precisely tunes its activity.
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U2 - 10.1093/NAR/GKAA084
DO - 10.1093/NAR/GKAA084
M3 - Article
C2 - 32170294
AN - SCOPUS:85084193271
SN - 0305-1048
VL - 48
SP - 4435
EP - 4447
JO - Nucleic acids research
JF - Nucleic acids research
IS - 8
ER -