Structure and function of the virulence-associated high-temperature requirement A of Mycobacterium tuberculosis

Nilofar N. MohamedMohaideen, Satheesh K. Palaninathan, Paul M. Morin, Brad J. Williams, Miriam Braunstein, Shane E. Tichy, Joseph Locker, David H. Russell, William R. Jacobs, James C. Sacchettini

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48 Scopus citations

Abstract

The high-temperature requirement A (HtrA) family of serine proteases has been shown to play an important role in the environmental and cellular stress damage control system in Escherichia coli. Mycobacterium tuberculosis (Mtb) has three putative HtrA-like proteases, HtrA1, HtrA2, and HtrA3. The deletion of htrA2 gives attenuated virulence in a mouse model of TB. Biochemical analysis reveals that HtrA2 can function both as a protease and as a chaperone. The three-dimensional structure of HtrA2 determined at 2.0 Å resolution shows that the protease domains form the central core of the trimer and the PDZ domains extend to the periphery. Unlike E. coli DegS and DegP, the protease is naturally active due to the formation of the serine protease-like catalytic triad and its uniquely designed oxyanion hole. Both protease and PDZ binding pockets of each HtrA2 molecule are occupied by autoproteolytic peptide products and reveal clues for a novel autoregulatory mechanism that might have significant importance in HtrA-associated virulence of Mtb.

Original languageEnglish (US)
Pages (from-to)6092-6102
Number of pages11
JournalBiochemistry
Volume47
Issue number23
DOIs
StatePublished - Jun 10 2008

ASJC Scopus subject areas

  • Biochemistry

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    MohamedMohaideen, N. N., Palaninathan, S. K., Morin, P. M., Williams, B. J., Braunstein, M., Tichy, S. E., Locker, J., Russell, D. H., Jacobs, W. R., & Sacchettini, J. C. (2008). Structure and function of the virulence-associated high-temperature requirement A of Mycobacterium tuberculosis. Biochemistry, 47(23), 6092-6102. https://doi.org/10.1021/bi701929m