Protein also known as:
Protective protein for beta-galactosidase.
Cleaved into:
Lysosomal protective protein 20 kDa chain; Lysosomal protective protein 32 kDa chain.
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.
J. Biol. Chem. 266, 14754-14762 (1991)[PubMed:1907282]
The protective protein was first discovered because of its deficiency in the metabolic storage disorder galactosialidosis. It associates with lysosomal beta-galactosidase and neuraminidase, toward which it exerts a protective function necessary for their stability and activity. Human and mouse protective proteins are homologous to yeast and plant serine carboxypeptidases. Here, we provide evidence that this protein has enzymatic activity similar to that of lysosomal cathepsin A: 1) overexpression of human and mouse protective proteins in COS-1 cells induces a 3-4-fold increase of cathepsin A-like activity; 2) this activity is reduced to approximately 1% in three galactosialidosis patients with different clinical phenotypes; 3) monospecific antibodies raised against human protective protein precipitate virtually all cathepsin A-like activity in normal human fibroblast extracts. Mutagenesis of the serine and histidine active site residues abolishes the enzymatic activity of the respective mutant protective proteins. These mutants, however, behave as the wild-type protein with regard to intracellular routing, processing, and secretion. In contrast, modification of the very conserved Cys60 residue interferes with the correct folding of the precursor polypeptide and, hence, its intracellular transport and processing. The secreted active site mutant precursors, endocytosed by galactosialidosis fibroblasts, restore beta-galactosidase and neuraminidase activities as effectively as wild-type protective protein. These findings indicate that the catalytic activity and protective function of the protective protein are distinct.
Esterase and deamidase activities at pH 7.0 and carboxypeptidase activity at pH 5.7 were markedly low or deficient in seven galactosialidosis fibroblast strains with deficient activity of "protective protein" for lysosomal beta-galactosidase and neuraminidase. No simultaneous deficiency of these three enzyme activities was observed in other lysosomal disease fibroblasts examined in this study. This result strongly suggests that "protective protein" is identical with a multifunctional protein with esterase/deamidase/carboxypeptidase activities and its mutation in galactosialidosis results in deficiency of these three enzyme activities.
The intracellular function of a specific protein to protect lysosomal beta-galactosidase and neuraminidase activities against proteases in human fibroblasts was studied. Beta-Galactosidase was purified from human placenta to different degrees; a preparation (A) contained also two concomitant proteins, and a highly purified preparation (B) contained only the mature beta-galactosidase. The protein concentrate of the culture medium of normal fibroblasts restored the activities of the deficient enzymes, beta-galactosidase and neuraminidase, in galactosialidosis cells. This effect was inhibited only by the anti-A anti-serum, and not by the anti-B antiserum. A 46-kilodalton protein, secreted from fibroblasts cultured in the presence of ammonium chloride, was detected again only by the anti-A antiserum, and not by the anti-B antiserum. It was concluded that this protein has a function to restore their activities in fibroblasts from galactosialidosis patients after being endocytosed from the culture medium.
Catalysis of the hydrolysis of a peptide bond not more than three residues from the C-terminus of a polypeptide chain by a catalytic mechanism that involves a catalytic triad consisting of a serine nucleophile that is activated by a proton relay involving an acidic residue (e.g. aspartate or glutamate) and a basic residue (usually histidine).
The directed movement of proteins in a cell, including the movement of proteins between specific compartments or structures within a cell, such as organelles of a eukaryotic cell.
J. Biol. Chem. 267, 17949-17956 (1992)[PubMed:1387645]
In lysosomes beta-galactosidase and neuraminidase acquire a stable and active conformation through their association with the protective protein. The latter is homologous to serine carboxypeptidases and has cathepsin A-like activity which is distinct from its protective function towards the two glycosidases. To define signals in the human protective protein important for its intracellular transport, and to determine the site of its association with beta-galactosidase, we have generated a set of mutated protective protein cDNAs carrying targeted base substitutions. These mutants were either singly transfected into COS-1 cells or cotransfected together with wild type human beta-galactosidase. We show that all point mutations cause either a complete or partial retention of the protective protein precursor in the endoplasmic reticulum. This abnormal accumulation leads to degradation of the mutant proteins probably in this compartment. Only the oligosaccharide chain on the 32-kDa subunit acquires the mannose 6-phosphate recognition marker, the one on the 20-kDa subunit seems to be merely essential for the stability of the mature protein. In cotransfection experiments, wild type beta-galactosidase and protective protein appear to assemble already as precursors, soon after synthesis, in the endoplasmic reticulum. Mutated protective protein precursors that are retained in the endoplasmic reticulum or pre-Golgi complex interact with and withhold normal beta-galactosidase molecules in the same compartments, thereby preventing their normal routing.
The intracellular function of a specific protein to protect lysosomal beta-galactosidase and neuraminidase activities against proteases in human fibroblasts was studied. Beta-Galactosidase was purified from human placenta to different degrees; a preparation (A) contained also two concomitant proteins, and a highly purified preparation (B) contained only the mature beta-galactosidase. The protein concentrate of the culture medium of normal fibroblasts restored the activities of the deficient enzymes, beta-galactosidase and neuraminidase, in galactosialidosis cells. This effect was inhibited only by the anti-A anti-serum, and not by the anti-B antiserum. A 46-kilodalton protein, secreted from fibroblasts cultured in the presence of ammonium chloride, was detected again only by the anti-A antiserum, and not by the anti-B antiserum. It was concluded that this protein has a function to restore their activities in fibroblasts from galactosialidosis patients after being endocytosed from the culture medium.
Enzyme which catalyzes hydrolysis reaction, i.e. the addition of the hydrogen and hydroxyl ions of water to a molecule with its consequent splitting into two or more simpler molecules.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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