Structure of human cathepsin D: comparison of inhibitor binding and subdomain displacement with other aspartic proteases.

Abstract

Cathepsin D (EC 3.4.23.5) (CatD) is an intracellular aspartic protease (AP) that is normally found in the lysosomes of higher eukaryotes. CatD shares two structural features with lysosomal enzymes that distinguish it from most secreted, extracellular APs. First, the mature enzyme from humans is found as a two-chain enzyme as a result of post-translational cleavage and removal of an insertion loop in the N-domain. Second, CatD contains phosphorylated, N-linked oligosaccharides that target the enzyme to lysosomes via man-nose-6-phosphate receptors (MPR). Interest in CatD as a target for drug design results from its association with several biological processes of therapeutic significance, particularly breast cancer and Alzheimer’s disease (Table 1). Recent studies have implicated CatD in the processing of (β-amyloid precursor protein to promote amyloid plaque formation in Alzheimer’s brain. Numerous studies of primary breast cancers have demonstrated that elevated levels of CatD were correlated with an increased risk of metastasis and shorter relapse-free survival. High levels of CatD produced in the vicinity of the growing tumor may degrade the extracellular matrix, either directly or indirectly by potentiating the activity of other tissue proteases, such as collagenase, and thereby promote tumor growth and metastasis. While a role for CatD or other APs in metastasis has been questioned by recent results that show a negative effect of pepstatin A in an in vitro invasion assay using breast cancer-derived MCF7 cells, new studies have revealed that elevated levels of CatD secretion in breast cancers correlate with tumor aggressiveness.