Cathepsin D

Structure

Gene

The CTSD gene is located at chromosome 11.

Protein

The catalytic sites of cathepsin D include two critical aspartic residues (amino acid 33 and 231) located on the 14 kDa and 34kDa chains. The ultimate form of mature cathepsin D is composed of 337 amino acid residues, 196 amino acid residues in the heavy chain and 141 in the light chain. These two chains are linked by the hydrophobic effect.

Function

The optimum pH for cathepsin D in vitro is 4.5-5.0. Cathepsin-D is an aspartic protease that depends critically on protonation of its active site Asp residue. Along with Asp-protonation, lower pH also leads to conformational switch in cathepsin-D: the N-terminal segment of the protease moves out of the active site as pH drops. Similar to other aspartic proteases, cathepsin D accommodates up to 8 amino acid residues in the binding cleft of the active site. The main physiological functions of cathepsin D consist of metabolic degradation of intracellular proteins, activation and degradation of polypeptide hormones and growth factors, activation of enzymatic precursors, processing of enzyme activators and inhibitors, brain antigen processing and regulation of programmed cell death. Cathepsin D can also be found in the extracellular space and it is one of the few cathepsins, that shows some activity at neutral pH. It is able to activate the growth factors VEGF-C and VEGF-D, which might partly explain its relevance for tumor progression.

Clinical significance

The NCLs present with progressive loss of visual function and neurodevelopmental decline, seizure, myoclonic jerks and premature death. The CTSD gene is one of the identified eight genes the deficiency of which is responsible for NCLs. It has been reported that a homozygous single nucleotide duplication in exon 6 could alter the reading frame and causes a premature stop codon at position 255. Over-expression of cathepsin D stimulates tumorigenicity and metastasis as well as initiation of tumor apoptosis. This protease has been regarded an independent marker of poor prognosis in breast cancer being correlated with the incidence of clinical metastasis. Knock-out of CTSD gene would cause intestinal necrosis and hemorrhage and increase apoptosis in thymus, indicating that cathepsin D is required in certain epithelial cells for tissue remodeling and renewal. It is also reported that there might be a strong effect for CTSD genotype on Alzheimer disease risk in male. Cathepsin D enzymatic activity induces hydrolytic modification of apolipoprotein B-100-containing lipoproteins, including LDL, which means it may be involved in atherosclerosis as well.

Interaction

• Pepstatin
• Transglutaminase 2
• HEBP1
• A2M
• Ceramide

References

References

1. (August 1985). "Cloning and sequence analysis of cDNA for human cathepsin D". Proceedings of the National Academy of Sciences of the United States of America.
2. "Entrez Gene: CTSD cathepsin D".
3. (April 1970). "Cathepsin D. Purification of isoenzymes from human and chicken liver". The Biochemical Journal.
4. (August 1989). "Cleavage of parathyroid hormone in macrophage endosomes illustrates a novel pathway for intracellular processing of proteins". The Journal of Biological Chemistry.
5. (August 1995). "Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells". The EMBO Journal.
6. (June 2006). "Another disorder finds its gene". Brain.
7. (April 1993). "Two crystal structures for cathepsin D: the lysosomal targeting signal and active site". The EMBO Journal.
8. (2008). "Human cathepsin D". Folia Histochemica et Cytobiologica.
9. (July 1988). "In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells". Cancer Research.
10. (March 2002). "Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D". The Journal of Biological Chemistry.
11. (October 1998). "Conformational switching in an aspartic proteinase". Nature Structural Biology.
12. (2004). "Protein Structure and Function". Oxford University Press.
13. (March 2006). "Cathepsin D is present in human eccrine sweat and involved in the postsecretory processing of the antimicrobial peptide DCD-1L". The Journal of Biological Chemistry.
14. (August 2003). "Lysosomal enzymes are released from cultured human macrophages, hydrolyze LDL in vitro, and are present extracellularly in human atherosclerotic lesions". Arteriosclerosis, Thrombosis, and Vascular Biology.
15. (1997). "Biological and diagnostic role of cathepsin D". Roczniki Akademii Medycznej W Bialymstoku.
16. (October 2008). "Cathepsin D—many functions of one aspartic protease". Critical Reviews in Oncology/Hematology.
17. (October 2004). "Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions". Journal of Cell Science.
18. (2019-05-17). "KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D". eLife.
19. (November 2005). "Assessing the utility of the stop dialysate flow method in patients receiving haemodiafiltration". Nephrology, Dialysis, Transplantation.
20. (April 2003). "Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer". The American Journal of Pathology.
21. (March 2001). "Non-replication of association between cathepsin D genotype and late onset Alzheimer disease". American Journal of Medical Genetics.
22. (December 2006). "Cathepsin D, a lysosomal protease, regulates ABCA1-mediated lipid efflux". The Journal of Biological Chemistry.
23. (May 1970). "Pepstatin, a new pepsin inhibitor produced by Actinomycetes". The Journal of Antibiotics.
24. (January 2013). "Depletion of cathepsin D by transglutaminase 2 through protein cross-linking promotes cell survival". Amino Acids.
25. (August 2011). "Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of formyl peptide receptor 3". Journal of Immunology.
26. (September 2006). "Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease". Journal of the Neurological Sciences.
27. (October 1999). "Cathepsin D targeted by acid sphingomyelinase-derived ceramide". The EMBO Journal.