Structure and function of the virulence-associated high-temperature requirement A of Mycobacterium tuberculosis.
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 A 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.
Mohamedmohaideen
Nilofar N
NN
Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA.
Palaninathan
Satheesh K
SK
Morin
Paul M
PM
Williams
Brad J
BJ
Braunstein
Miriam
M
Tichy
Shane E
SE
Locker
Joseph
J
Russell
David H
DH
Jacobs
William R
WR
Sacchettini
James C
JC
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D005784:Gene Amplification; D006360:Heat-Shock Proteins / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D033903:Periplasmic Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014376:Tuberculosis / Q000201:enzymology; D014774:Virulence
D001426:Bacterial Proteins; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; D033903:Periplasmic Proteins; C061682:DegP protease; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse