tailieunhanh - Báo cáo khoa học: The effect of HAMP domains on class IIIb adenylyl cyclases from Mycobacterium tuberculosis

The genesRv1318c, Rv1319c, Rv1320cand Rv3645 1 of Mycobacterium tuberculosisare predicted to code for four out of 15 adenylyl cyclases in this pathogen. The proteins consist of a membrane anchor, a HAMP region and a class IIIb adenylyl cyclase catalytic domain. Expression and purification of the isolated catalytic domains yielded aden-ylyl cyclase activity for all four recombinant proteins. Expression of the HAMP region fused to the catalytic domain increased activity in Rv3645 21-fold and slightly reduced activity in Rv1319c by 70%, demonstrating iso-form-specific effects of the HAMP domains. . | Eur. J. Biochem. 271 2446-2451 2004 FEBS 2004 doi The effect of HAMP domains on class Illb adenylyl cyclases from Mycobacterium tuberculosis Jiirgen U. Linder Arne Hammer and Joachim E. Schultz Abteilung Pharmazeutische Biochemie Fakulteit fur Chemie und Pharmazie Universitat Tubingen Morgenstelle Tubingen Germany The genes Rv1318c Rv1319c Rv1320c and Rv3645 of Mycobacterium tuberculosis are predicted to code for four out of 15 adenylyl cyclases in this pathogen. The proteins consist of a membrane anchor a HAMP region and a class Illb adenylyl cyclase catalytic domain. Expression and purification of the isolated catalytic domains yielded adenylyl cyclase activity for all four recombinant proteins. Expression of the HAMP region fused to the catalytic domain increased activity in Rv3645 21-fold and slightly reduced activity in Rv1319c by 70 demonstrating isoform-specific effects of the HAMP domains. Point mutations were generated to remove predicted hydrophobic protein surfaces in the HAMP domains. The mutations further stimulated activity in Rv3645 eight-fold whereas the effect on Rv1319c was marginal. Thus HAMP domains can act directly as modulators of adenylyl cyclase activity. The modulatory properties of the HAMP domains were confirmed by swapping them between Rv1319c and Rv3645. The data indicate that in the mycobacterial adenylyl cyclases the HAMP domains do not display a uniform regulatory input but instead each form a distinct signaling unit with its adjoining catalytic domain. Keywords adenylyl cyclase HAMP-domain Mycobacterium tuberculosis. Synthesis of the universal second messenger cAMP is accomplished by a plethora of adenylyl cyclases ACs which are currently arranged in five classes of unrelated primary structure 1-3 . The vast majority of ACs fall into class III which in turn has been subdivided recently into four subclasses IIIa-d 4 . The catalytic domain of these ACs also designated as the cyclase homology domain CHD

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