4az3

Structural highlights

Disease

[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.^{[1] [2] [3] [4]}

Function

[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.^[5]

References

1. ↑ 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
2. ↑ Shimmoto M, Fukuhara Y, Itoh K, Oshima A, Sakuraba H, Suzuki Y. Protective protein gene mutations in galactosialidosis. J Clin Invest. 1993 Jun;91(6):2393-8. PMID:8514852 doi:http://dx.doi.org/10.1172/JCI116472
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ Ruf S, Buning C, Schreuder H, Horstick G, Linz W, Olpp T, Pernerstorfer J, Hiss K, Kroll K, Kannt A, Kohlmann M, Linz D, Hubschle T, Rutten H, Wirth K, Schmidt T, Sadowski T. Novel beta-Amino Acid Derivatives as Inhibitors of Cathepsin A. J Med Chem. 2012 Sep 13;55(17):7636-49. Epub 2012 Aug 16. PMID:22861813 doi:http://dx.doi.org/10.1021/jm300663n