Lee, Ho JunLang, P. ThereseFortune, SarahSassetti, Christopher M.Alber, Tom2013-12-132012Lee, Ho Jun, P. Therese Lang, Sarah M. Fortune, Christopher M. Sassetti, and Tom Alber. 2012. Cyclic AMP regulation of protein lysine acetylation in mycobacterium tuberculosis. Nature Structural and Molecular Biology 19(8): 811-8.1545-9993http://nrs.harvard.edu/urn-3:HUL.InstRepos:11379655Protein lysine acetylation networks can regulate central processes such as carbon metabolism and gene expression in bacteria. In Escherichia coli, cyclic-AMP (cAMP) regulates protein lysine acetyltransferase (PAT) activity at the transcriptional level, but in Mycobacterium tuberculosis, fusion of a cyclic-nucleotide binding domain to a Gcn5-like PAT domain enables direct cAMP control of protein acetylation. Here we describe the allosteric activation mechanism of M. tuberculosis PAT. The crystal structures of the auto-inhibited and cAMP-activated PAT reveal that cAMP binds to a cryptic site in the regulatory domain over 32 Å from the catalytic site. An extensive conformational rearrangement relieves auto-inhibition by a substrate-mimicking lid that covers the protein-substrate binding surface. A steric double latch couples the domains by harnessing a classic, cAMP-mediated, conformational switch. The structures suggest general features that enable the evolution of long-range communication between linked domains.en-USevolution of allosteric regulationRv0998domain couplingconformational changeRingerJournal Article2013-12-1310.1038/nsmb.2318