Adenylyl Cyclase in complex with alpha,beta-methylene-ATP
Spirulina platensis (cyanobacteria)
In our body, signal transmitters ("first messenger") such as neurotransmitters, hormones and cytokines are recognized by receptors in the cell membrane. Then the signals in the membrane are converted to various forms. A fine example is "second messenger", which is diffusible, and enable the signal to reach the distant places in the cell. cAMP is a second messenger which activates protein kinases and transcription factors. Its production is catalyzed by adenylyl cyclases. Adenylyl cyclases are divided in two groups, transmembrane adenylyl cyclases (tmAC) and soluble adenylyl cyclases (sAC). Despite their different regulation and localization, they belong to the family of nucleotidyl cyclase class III because of the conserved active site amino acid sequence.
The structure described here is the active domain of sAC homologue CyaC from a cyanobacterium (Spirulina platensis). sACs localize in the mitochondrion and the nucleus and activated by calcium and bicarbonate, whereas tmACs localize on the plasma membrane and regulated by G proteins. The structural characteristic of CyaC is the 180 degrees rotational symmetric homodimer. The catalytic center exists within the clefts made by the two subunits, an alpha-helix of one subunit and a loop between the beta-sheets of another. An ATP and two divalent cations bind to the catalytic center. A calcium (or a magnesium) links the beta- and gamma-phosphates of ATP, a water, D1017, I1018, and D1061 of CyaC, and stabilizes the open state of the active site. In contrast, bicarbonate increases the catalytic rate by closing the active site and recruiting a second divalent cation (magnesium). This conformational change induces the separation of alpha- and beta-phosphate of ATP, and cAMP production is accelerated by the magnesium. The mechanisms of calcium and bicarbonate sensing in CyaC will provide a reaction model involving active site closure and metal recruitement that may be universal for nucleotidyl cyclase class III proteins.
Protein Data Bank (PDB)
author: Daisuke Ino