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

Research output: Contribution to journalArticle

48 Citations (Scopus)

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

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Mycobacterium tuberculosis
Virulence
Peptide Hydrolases
Temperature
Serine Proteases
Escherichia coli
PDZ Domains
Control systems
Peptides
Molecules

ASJC Scopus subject areas

  • Biochemistry

Cite this

MohamedMohaideen, N. N., Palaninathan, S. K., Morin, P. M., Williams, B. J., Braunstein, M., Tichy, S. E., ... 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

Structure and function of the virulence-associated high-temperature requirement A of Mycobacterium tuberculosis. / MohamedMohaideen, Nilofar N.; Palaninathan, Satheesh K.; Morin, Paul M.; Williams, Brad J.; Braunstein, Miriam; Tichy, Shane E.; Locker, Joseph; Russell, David H.; Jacobs, William R.; Sacchettini, James C.

In: Biochemistry, Vol. 47, No. 23, 10.06.2008, p. 6092-6102.

Research output: Contribution to journalArticle

MohamedMohaideen, NN, Palaninathan, SK, Morin, PM, Williams, BJ, Braunstein, M, Tichy, SE, Locker, J, Russell, DH, Jacobs, WR & Sacchettini, JC 2008, 'Structure and function of the virulence-associated high-temperature requirement A of Mycobacterium tuberculosis', Biochemistry, vol. 47, no. 23, pp. 6092-6102. https://doi.org/10.1021/bi701929m
MohamedMohaideen NN, Palaninathan SK, Morin PM, Williams BJ, Braunstein M, Tichy SE et al. Structure and function of the virulence-associated high-temperature requirement A of Mycobacterium tuberculosis. Biochemistry. 2008 Jun 10;47(23):6092-6102. https://doi.org/10.1021/bi701929m
MohamedMohaideen, Nilofar N. ; Palaninathan, Satheesh K. ; Morin, Paul M. ; Williams, Brad J. ; Braunstein, Miriam ; Tichy, Shane E. ; Locker, Joseph ; Russell, David H. ; Jacobs, William R. ; Sacchettini, James C. / Structure and function of the virulence-associated high-temperature requirement A of Mycobacterium tuberculosis. In: Biochemistry. 2008 ; Vol. 47, No. 23. pp. 6092-6102.
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