A mycobacterial cyclic AMP phosphodiesterase that moonlights as a modifier of cell wall permeability

Marjetka Podobnik, Richa Tyagi, Nishad Matange, Urška Dermol, Arun K. Gupta, Rohini Mattoo, Kothandaraman Seshadri, Sandhya S. Visweswariah

Research output: Contribution to journalArticle

Abstract

Mycobacterium tuberculosis utilizes many mechanisms to establish itself within the macrophage, and bacterially derived cAMP is important in modulating the host cellular response. Although the genome of M. tuberculosis is endowed with a number of mammalian-like adenylyl cyclases, only a single cAMP phosphodiesterase has been identified that can decrease levels of cAMP produced by the bacterium. We present the crystal structure of the full-length and sole cAMP phosphodiesterase, Rv0805, found in M. tuberculosis, whose orthologs are present only in the genomes of slow growing and pathogenic mycobacteria. The dimeric core catalytic domain of Rv0805 adopts a metallophosphoesterase-fold, and the C-terminal region builds the active site and contributes to multiple substrate utilization. Localization of Rv0805 to the cell wall is dependent on its C terminus, and expression of either wild type or mutationally inactivated Rv0805 in M. smegmatis alters cell permeability to hydrophobic cytotoxic compounds. Rv0805 may therefore play a key role in the pathogenicity of mycobacteria, not only by hydrolyzing bacterial cAMP, but also by moonlighting as a protein that can alter cell wall functioning.

Original languageEnglish (US)
Pages (from-to)32846-32857
Number of pages12
JournalJournal of Biological Chemistry
Volume284
Issue number47
DOIs
StatePublished - Nov 20 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Podobnik, M., Tyagi, R., Matange, N., Dermol, U., Gupta, A. K., Mattoo, R., Seshadri, K., & Visweswariah, S. S. (2009). A mycobacterial cyclic AMP phosphodiesterase that moonlights as a modifier of cell wall permeability. Journal of Biological Chemistry, 284(47), 32846-32857. https://doi.org/10.1074/jbc.M109.049635