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Báo cáo khoa học: Activation of cathepsin D by glycosaminoglycans

We have previously shown that heparin can increase the activity of the pro-enzyme form of Alzheimer’s b-site amyloid precursor protein cleaving enzyme 1 (BACE1). Cathepsin D (CD) is a member of the aspartic prote-ase family and has sequence similarity to BACE1. | ỊFEBS Journal Activation of cathepsin D by glycosaminoglycans Marie Beckman1 2 Craig Freeman3 Christopher R. Parish3 and David H. Small4 1 Department of Biochemistry and Molecular Biology Monash University Clayton Australia 2 Life Sciences Sodertorn University Huddinge Sweden 3 Division of Immunology and Genetics The John Curtin Schoolof MedicalResearch The Australian National university Canberra Australia 4 Laboratory of Molecular Neurobiology Menzies Research Institute University of Tasmania Hobart Australia Keywords aspartic protease cathepsin D glycosaminoglycan heparin proteolytic activity Correspondence M. Beckman Life Sciences Sodertorn University SE-141 89 Huddinge Sweden Fax 46 8 6084510 Tel 46 8 6084731 E-mail marie.beckman@sh.se Received 1 April2009 revised 8 September 2009 accepted 16 October 2009 doi 10.1111 j.1742-4658.2009.07444.x We have previously shown that heparin can increase the activity of the proenzyme form of Alzheimer s b-site amyloid precursor protein cleaving enzyme 1 BACE1 . Cathepsin D CD is a member of the aspartic protease family and has sequence similarity to BACE1. Therefore we examined whether heparin and other glycosaminoglycans GAGs can influence the activity of CD. Heparin and other GAGs were found to stimulate the activity of recombinant proCD. Desulfation of heparin almost abolished the stimulation indicating that sulfate groups were important for the stimulatory effect. In addition the stimulation was dependent on the length of the GAG chain as larger GAGs were more potent in their ability to stimulate proCD than shorter fragments. In the presence of heparin limited autocatalytic proteolysis of the proenzyme was increased suggesting that heparin increases the activity of proCD by accelerating the conversion of proCD which has little activity to pseudoCD an active form lacking residues 1-26 of the prodomain. Furthermore the activity of spleen-derived mature CD which lacks the entire 44 amino acid residue prodomain was also .