Crystal structure of cathepsin X: a flip-flop of the ring of His23 allows carboxy-monopeptidase and carboxy-dipeptidase activity of the protease

Crystal structure of cathepsin X: a flip-flop of the ring of His23 allows carboxy-monopeptidase and carboxy-dipeptidase activity of the protease

Author Guncar, Gregor Google Scholar
Klemencic, Ivica Google Scholar
Turk, Boris Google Scholar
Turk, Vito Google Scholar
Carmona, Adriana Karaoglanovic Autor UNIFESP Google Scholar
Juliano, Luiz Autor UNIFESP Google Scholar
Turk, Dusan Google Scholar
Institution Jozef Stefan Inst
Universidade Federal de São Paulo (UNIFESP)
Abstract Background: Cathepsin X is a widespread, abundantly expressed papain-like mammalian lysosomal cysteine protease. It exhibits carboxy-monopeptidase as well as carboxy-dipeptidase activity and shares a similar activity profile with cathepsin B. the latter has been implicated in normal physiological events as well as in various pathological states such as rheumatoid arthritis, Alzheimer's disease and cancer progression. Thus the question is raised as to which of the two enzyme activities has actually been monitored.Results: the crystal structure of human cathepsin X has been determined at 2.67 Angstrom resolution. the structure shares the common features of a papain-like enzyme fold, but with a unique active site. the most pronounced feature of the cathepsin X structure is the mini-loop that includes a short three-residue insertion protruding into the active site of the protease. the residue Tyr27 on one side of the loop forms the surface of the S1 substrate-binding site, and His23 on the other side modulates both carboxy-monopeptidase as well as carboxy-dipeptidase activity of the enzyme by binding the C-terminal carboxyl group of a substrate in two different sidechain conformations.Conclusions: the structure of cathepsin X exhibits a binding surface that will assist in the design of specific inhibitors of cathepsin X as well as of cathepsin B and thereby help to clarify the physiological roles of both proteases.
Keywords Alzheimer's disease
carboxypeptidase
cathepsin B
cathepsin X
papain-like cysteine protease
Language English
Date 2000-03-15
Published in Structure With Folding & Design. London: Current Biology Ltd, v. 8, n. 3, p. 305-313, 2000.
ISSN 0969-2126 (Sherpa/Romeo, impact factor)
Publisher Current Biology Ltd
Extent 305-313
Origin http://dx.doi.org/10.1016/S0969-2126(00)00108-8
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000085943900012
URI http://repositorio.unifesp.br/handle/11600/26272

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