The structure of a pH-sensing mycobacterial adenylyl cyclase holoenzyme.
Class III adenylyl cyclases contain catalytic and regulatory domains, yet structural insight into their interactions is missing. We show that the mycobacterial adenylyl cyclase Rv1264 is rendered a pH sensor by its N-terminal domain. In the structure of the inhibited state, catalytic and regulatory domains share a large interface involving catalytic residues. In the structure of the active state, the two catalytic domains rotate by 55 degrees to form two catalytic sites at their interface. Two alpha helices serve as molecular switches. Mutagenesis is consistent with a regulatory role of the structural transition, and we suggest that the transition is regulated by pH.
Tews
Ivo
I
Biochemiezentrum der Universität Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany. ivo.tews@bzh.uni-heidelberg.de
Findeisen
Felix
F
Sinning
Irmgard
I
Schultz
Anita
A
Schultz
Joachim E
JE
Linder
Jürgen U
JU
D000255:Adenosine Triphosphate / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D019281:Dimerization; D020035:Holoenzymes / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D000067956:Adenylyl Cyclase Inhibitors; D001426:Bacterial Proteins; D020035:Holoenzymes; D000255:Adenosine Triphosphate; D000262:Adenylyl Cyclases; C458521:Rv1264 protein, Mycobacterium tuberculosis