Structural basis of adenylyl cyclase 9 activation
Chao Qi1,2, Pia Lavriha2, Ved Mehta1,2
1Institute of Molecular Biology and Biophysics, ETH, Zurich, Switzerland.
Nature Communications
|February 25, 2022
Summary
Adenylyl cyclase 9 (AC9) undergoes structural changes upon activator binding. These rearrangements, particularly around the forskolin site, are crucial for enzyme activation, revealing key insights into AC9 function.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Adenylyl cyclase 9 (AC9) synthesizes cyclic AMP (cAMP) from ATP.
- AC9 is regulated by G protein Gαs, forskolin, and autoinhibition via its C-terminus.
- Understanding AC9 conformational changes upon activation is crucial but poorly understood.
Purpose of the Study:
- To elucidate the structural mechanisms of AC9 activation.
- To investigate conformational changes induced by different activators and inhibitors.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine structures of AC9 in various states.
- Structures were obtained for AC9 bound to inhibitors, artificial activators (DARPin C4), and Gαs.
Main Results:
- Cryo-EM structures revealed AC9 in distinct states, including bound to MANT-GTP, DARPin C4, and Gαs.
- The artificial activator DARPin C4 binds to a site overlapping with Gαs binding.
- Structural comparisons highlight secondary structure rearrangements near the forskolin binding site as critical for activation.
Conclusions:
- Secondary structure rearrangements in the forskolin binding region are essential for AC9 activation.
- The study provides structural insights into the activation mechanism of Adenylyl cyclase 9.
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