[PPGB_HUMAN] Defects in CTSA are the cause of galactosialidosis (GSL) [MIM:256540]. A lysosomal storage disease associated with a combined deficiency of beta-galactosidase and neuraminidase, secondary to a defect in cathepsin A. All patients have clinical manifestations typical of a lysosomal disorder, such as coarse facies, cherry red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes. Three phenotypic subtypes are recognized. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile type is characterized by hepatosplenomegaly, growth retardation, cardiac involvement, and a normal or mildly affected mental state. The juvenile/adult form is characterized by myoclonus, ataxia, angiokeratoma, mental retardation, neurologic deterioration, absence of visceromegaly, and long survival.
[PPGB_HUMAN] Protective protein appears to be essential for both the activity of beta-galactosidase and neuraminidase, it associates with these enzymes and exerts a protective function necessary for their stability and activity. This protein is also a carboxypeptidase and can deamidate tachykinins.
BACKGROUND: The human 'protective protein' (HPP) forms a multi-enzyme complex with beta-galactosidase and neuraminidase in the lysosomes, protecting these two glycosidases from degradation. In humans, deficiency of HPP leads to the lysosomal storage disease galactosialidosis. Proteolytic cleavage of the precursor form of HPP involves removal of a 2 kDa excision peptide and results in a carboxypeptidase activity. The physiological relevance of this activity is, as yet, unknown. RESULTS: The crystal structure of the 108 kDa dimer of the precursor HPP has been elucidated by making extensive use of twofold density averaging. The monomer consists of a 'core' domain and a 'cap' domain. Comparison with the distantly related wheat serine carboxypeptidase dimer shows that the two subunits in the HPP dimer differ by 15 degrees in mutual orientation. Also, the helical subdomain forming part of the cap domains is very different. In addition, the HPP precursor cap domain contains a 'maturation' subdomain of 49 residues which fills the active-site cleft. Merely removing the 'excision' peptide located in the maturation subdomain does not render the catalytic triad solvent accessible. CONCLUSIONS: The activation mechanism of HPP is unique among proteases with known structure. It differs from the serine proteases in that the active site is performed in the zymogen, but is blocked by a maturation subdomain. In contrast to the zinc metalloproteases and aspartic proteases, the chain segment physically rendering the catalytic triad solvent inaccessible in HPP is not cleaved off to form the active enzyme. The activation must be a multi-step process involving removal of the excision peptide and major conformational changes of the maturation subdomain, whereas the conformation of the enzymatic machinery is probably almost, or completely, unaffected.
Three-dimensional structure of the human 'protective protein': structure of the precursor form suggests a complex activation mechanism.,Rudenko G, Bonten E, d'Azzo A, Hol WG Structure. 1995 Nov 15;3(11):1249-59. PMID:8591035
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Zhou XY, Galjart NJ, Willemsen R, Gillemans N, Galjaard H, d'Azzo A. A mutation in a mild form of galactosialidosis impairs dimerization of the protective protein and renders it unstable. EMBO J. 1991 Dec;10(13):4041-8. PMID:1756715
↑ Zhou XY, van der Spoel A, Rottier R, Hale G, Willemsen R, Berry GT, Strisciuglio P, Morrone A, Zammarchi E, Andria G, d'Azzo A. Molecular and biochemical analysis of protective protein/cathepsin A mutations: correlation with clinical severity in galactosialidosis. Hum Mol Genet. 1996 Dec;5(12):1977-87. PMID:8968752
↑ Takiguchi K, Itoh K, Shimmoto M, Ozand PT, Doi H, Sakuraba H. Structural and functional study of K453E mutant protective protein/cathepsin A causing the late infantile form of galactosialidosis. J Hum Genet. 2000;45(4):200-6. PMID:10944848 doi:10.1007/s100380070027
↑ Galjart NJ, Morreau H, Willemsen R, Gillemans N, Bonten EJ, d'Azzo A. Human lysosomal protective protein has cathepsin A-like activity distinct from its protective function. J Biol Chem. 1991 Aug 5;266(22):14754-62. PMID:1907282
↑ Rudenko G, Bonten E, d'Azzo A, Hol WG. Three-dimensional structure of the human 'protective protein': structure of the precursor form suggests a complex activation mechanism. Structure. 1995 Nov 15;3(11):1249-59. PMID:8591035