Two crystal structures for cathepsin D: the lysosomal targeting signal and active site
- PMID: 8467789
- PMCID: PMC413340
- DOI: 10.1002/j.1460-2075.1993.tb05774.x
Two crystal structures for cathepsin D: the lysosomal targeting signal and active site
Abstract
Two crystal structures are described for the lysosomal aspartic protease cathepsin D (EC 3.4.23.5). The molecular replacement method was used with X-ray diffraction data to 3 A resolution to produce structures for human spleen cathepsin D and for bovine liver cathepsin D complexed with the 6-peptide inhibitor pepstatin A. The lysosomal targeting region of cathepsin D defined by previous expression studies [Barnaski et al. (1990) Cell, 63, 281-219] is located in well defined electron density on the surface of the molecules. This region includes the putative binding site of the cis-Golgi phosphotransferase which is responsible for the initial sorting step for soluble proteins destined for lysosomes by phosphorylating the carbohydrates on these molecules. Carbohydrate density is visible at both expected positions on the cathepsin D molecules and, at the best defined position, four sugar residues extend towards the lysosomal targeting region. The active site of the protease and the active site cleft substrate binding subsites are described using the pepstatin inhibited structure. The model geometry for human cathepsin D has rms deviations from ideal of bonds and angles of 0.013 A and 3.2 degrees respectively. For bovine cathepsin D the corresponding figures are 0.014 A and 3.3 degrees. The crystallographic residuals (R factors) are 16.1% and 15.8% for the human and inhibited bovine cathepsin D models respectively. The free R factors, calculated with 10% of the data reserved for testing the models and not used for refinement, are 25.1% and 24.1% respectively.
Similar articles
-
Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design.Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6796-800. doi: 10.1073/pnas.90.14.6796. Proc Natl Acad Sci U S A. 1993. PMID: 8393577 Free PMC article.
-
Cathepsin D crystal structures and lysosomal sorting.Adv Exp Med Biol. 1995;362:193-200. doi: 10.1007/978-1-4615-1871-6_23. Adv Exp Med Biol. 1995. PMID: 8540319 No abstract available.
-
Crystal structure of porcine cathepsin H determined at 2.1 A resolution: location of the mini-chain C-terminal carboxyl group defines cathepsin H aminopeptidase function.Structure. 1998 Jan 15;6(1):51-61. doi: 10.1016/s0969-2126(98)00007-0. Structure. 1998. PMID: 9493267
-
Isolation and sequencing of a cDNA clone encoding rat liver lysosomal cathepsin D and the structure of three forms of mature enzymes.Biochem Biophys Res Commun. 1991 Aug 30;179(1):190-6. doi: 10.1016/0006-291x(91)91353-e. Biochem Biophys Res Commun. 1991. PMID: 1883350
-
Cathepsin D: the lysosomal aspartic proteinase.Ciba Found Symp. 1979;(75):37-50. doi: 10.1002/9780470720585.ch3. Ciba Found Symp. 1979. PMID: 399896 Review.
Cited by
-
A replacement of the active-site aspartic acid residue 293 in mouse cathepsin D affects its intracellular stability, processing and transport in HEK-293 cells.Biochem J. 2003 Jan 1;369(Pt 1):55-62. doi: 10.1042/BJ20021226. Biochem J. 2003. PMID: 12350228 Free PMC article.
-
Oxidation of Cathepsin D by Hydroxy Radical: Its Effect on Enzyme Structure and Activity against Myofibrillar Proteins Extracted from Coregonus peled.Molecules. 2023 Jun 29;28(13):5117. doi: 10.3390/molecules28135117. Molecules. 2023. PMID: 37446781 Free PMC article.
-
Cathepsin D--many functions of one aspartic protease.Crit Rev Oncol Hematol. 2008 Oct;68(1):12-28. doi: 10.1016/j.critrevonc.2008.02.008. Epub 2008 Apr 8. Crit Rev Oncol Hematol. 2008. PMID: 18396408 Free PMC article. Review.
-
New multienzymatic complex formed between human cathepsin D and snake venom phospholipase A2.J Venom Anim Toxins Incl Trop Dis. 2022 Nov 4;28:e20220002. doi: 10.1590/1678-9199-JVATITD-2022-0002. eCollection 2022. J Venom Anim Toxins Incl Trop Dis. 2022. PMID: 36404954 Free PMC article.
-
Cathepsin D-Managing the Delicate Balance.Pharmaceutics. 2021 Jun 5;13(6):837. doi: 10.3390/pharmaceutics13060837. Pharmaceutics. 2021. PMID: 34198733 Free PMC article. Review.
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases