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Inhibition of R-Lytic Protease by Pro Region C-Terminal Steric Occlusion of the Active Site

Summary: Inhibition of R-Lytic Protease by Pro Region C-Terminal Steric Occlusion of the
Active Site
Julie L. Sohl, Andrew K. Shiau, Stephen D. Rader, Barry J. Wilk,| and David A. Agard*,,
Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, Graduate Group in Biophysics,
UniVersity of California at San Francisco, San Francisco, California 94143-0448
ReceiVed September 17, 1996; ReVised Manuscript ReceiVed January 23, 1997X
ABSTRACT: R-Lytic protease, a chymotrypsin-like serine protease, is synthesized with an N-terminal 166
amino acid pro region which is absolutely required for folding of the protease. The pro region is also the
most potent inhibitor of the protease known with a Ki of 10-10 M. Compared to its role in the folding
reaction, relatively little is known about the mechanism by which the pro region inhibits the mature protease.
While proteinaceous protease inhibitors generally function by occluding the active sites of their respective
targets [Bode, W., & Huber, R. (1992) Eur. J. Biochem. 204, 433-451], the pro region of R-lytic protease
with its dual roles in folding and inhibition might be expected to show a novel mechanism of inhibition.
However, experiments that probe both the structural and enzymatic consequences of pro region binding
indicate that the pro region does not measurably distort the protease active site. Instead, the catalytic site
is fully functional in the complex. Pro region inhibition of the protease is due to simple steric obstruction;
the pro region C-terminus lies in the substrate binding sites of the protease. The implications of these
results are discussed with regard to R-lytic protease maturation and folding. In addition, the proposed
mechanism of R-lytic protease pro region inhibition is discussed with respect to data from other pro
region families.


Source: Agard, David - Department of Biochemistry and Biophysics, University of California at San Francisco
Rader, Stephen - Chemistry Program, University of Northern British Columbia


Collections: Biology and Medicine; Biotechnology; Chemistry