Site-2 protease substrate specificity and coupling in trans by a PDZ-substrate adapter protein.
Site-2 proteases (S2Ps) are intramembrane metalloproteases that cleave transmembrane substrates in all domains of life. Many S2Ps, including human S2P and Mycobacterium tuberculosis Rip1, have multiple substrates in vivo, which are often transcriptional regulators. However, S2Ps will also cleave transmembrane sequences of nonsubstrate proteins, suggesting additional specificity determinants. Many S2Ps also contain a PDZ domain, the function of which is poorly understood. Here, we identify an M. tuberculosis protein, PDZ-interacting protease regulator 1 (Ppr1), which bridges between the Rip1 PDZ domain and anti-sigma factor M (Anti-SigM), a Rip1 substrate, but not Anti-SigK or Anti-SigL, also Rip1 substrates. In vivo analyses of Ppr1 function indicate that it prevents nonspecific activation of the Rip1 pathway while coupling Rip1 cleavage of Anti-SigM, but not Anti-SigL, to site-1 proteolysis. Our results support a model of S2P substrate specificity in which a substrate-specific adapter protein tethers the S2P to its substrate while holding the protease inactive through its PDZ domain.
Immunology Program, Sloan-Kettering Institute, New York, NY 10021.
Jessica S
JS
Schneider
Shilpa P
SP
Reddy
Hock Y
HY
E
Henry W
HW
Evans
Michael S
MS
Glickman
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D054731:PDZ Domains / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D012808:Sigma Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D013379:Substrate Specificity; D020798:Two-Hybrid System Techniques; D015003:Yeasts
D001426:Bacterial Proteins; D012808:Sigma Factor; D045726:Metalloproteases
Sigma factor; Tuberculosis; intramembrane proteolysis; signal transduction