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Review
. 2014:2014:309718.
doi: 10.1155/2014/309718. Epub 2014 Dec 21.

Cysteine cathepsin activity regulation by glycosaminoglycans

Marko Novinec  1 , Brigita Lenarčič  2 , Boris Turk  3
Affiliations
Review

Cysteine cathepsin activity regulation by glycosaminoglycans

Marko Novinec et al. Biomed Res Int. 2014.

Abstract

Cysteine cathepsins are a group of enzymes normally found in the endolysosomes where they are primarily involved in intracellular protein turnover but also have a critical role in MHC II-mediated antigen processing and presentation. However, in a number of pathologies cysteine cathepsins were found to be heavily upregulated and secreted into extracellular milieu, where they were found to degrade a number of extracellular proteins. A major role in modulating cathepsin activities play glycosaminoglycans, which were found not only to facilitate their autocatalytic activation including at neutral pH, but also to critically modulate their activities such as in the case of the collagenolytic activity of cathepsin K. The interaction between cathepsins and glycosaminoglycans will be discussed in more detail.

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Figures

Figure 1
Figure 1
The papain-like peptidase fold illustrated on the crystal structure of papain. The protein is shown in cartoon representation and the position of the active site cleft is marked by an arrow. Catalytic residues Cys and His are shown as yellow and blue spheres, respectively. Coordinates were obtained from the Protein Data Bank under accession code 1PPN. The image was created with PyMOL (Schrödinger, LLC, Portland, OR, USA).
Figure 2
Figure 2
Interactions between human cathepsin K and GAGs. (a) Crystal structure of the cathepsin K/chondroitin-4-sulfate (C4S) complex. The protein is shown in cartoon representation and C4S is shown as sticks. (b) Conformational change in C4S upon binding to cathepsin K. (c) Detailed representation of the interaction in panel (a). C4S is shown as sticks. The backbone of cathepsin K is shown as ribbons and residues that interact with C4S are shown as sticks. (d) Location of the predicted second heparin-binding site in cathepsin K. Positively charged residues proposed to interact with heparin are shown as blue sticks. For orientation, C4S bound at the first binding site is shown as sticks. The position of the active site cleft is marked by an arrow. Coordinates of the cathepsin K/C4S complex were retrieved from the Protein Data Bank under accession code 3C9E. The solution structure of C4S was modeled using data from [14]. All images were created with PyMOL.
Figure 3
Figure 3
Predicted GAG-binding sites in papain-like peptidases. (a) Three predicted CS-binding sites in cathepsin S. (b) Two predicted HS/HP-binding sites in cathepsin B. (c) The conserved GAG-binding motif in papain. Predicted sites are shown in circles and positively charged residues at each site are shown as blue sticks and labeled. The position of the active site cleft is marked by an arrow. All coordinates were obtained from the Protein Data Bank (accession codes: 1NQC for cathepsin S, 3AI8 for cathepsin B, and 1PPN for papain, resp.). All images were created with PyMOL.
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References

    1. Rawlings N. D., Barrett A. J., Bateman A. MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Research. 2012;40(1):D343–D350. doi: 10.1093/nar/gkr987. - DOI - PMC - PubMed
    1. Rossi A., Deveraux Q., Turk B., Sali A. Comprehensive search for cysteine cathepsins in the human genome. Biological Chemistry. 2004;385(5):363–372. doi: 10.1515/BC.2004.040. - DOI - PubMed
    1. Turk V., Stoka V., Vasiljeva O., Renko M., Sun T., Turk B., Turk D. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochimica et Biophysica Acta—Proteins and Proteomics. 2012;1824(1):68–88. doi: 10.1016/j.bbapap.2011.10.002. - DOI - PMC - PubMed
    1. Novinec M., Lenarčič B. Papain-like peptidases: Structure, function, and evolution. Biomolecular Concepts. 2013;4(3):287–308. doi: 10.1515/bmc-2012-0054. - DOI - PubMed
    1. Vasiljeva O., Reinheckel T., Peters C., Turk D., Turk V., Turk B. Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Current Pharmaceutical Design. 2007;13(4):387–403. doi: 10.2174/138161207780162962. - DOI - PubMed

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