Structure of Full-Length cDNA Coding for Sulfatide Activator, a Co-β-Glucosidase and Two Other Homologous Proteins: Two Alternate Forms of the Sulfatide Activator1

Nakano, Takeshi; Sandhoff, Konrad; Stumper, Judith; Christomanou, H.; Suzuki, Kazuyuki

doi:10.1093/oxfordjournals.jbchem.a122629

Cited by 133 publications

(75 citation statements)

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“…1 Among them, the four saposins have a common precursor. The prosaposin gene (PSAP) [2][3][4] (cDNA sequence in GenBank, accession number D00422; genomic DNA sequence in GenBank, accession number M86181), encodes a polypeptide, glycosylated at five sites, which is transported to lysosomes where it is processed to produce the four mature saposins. 1 The physiological role of saposin A (sap-A) and saposin-D (sap-D) has not been completely elucidated.…”

Section: Introductionmentioning

confidence: 99%

An Asn > Lys substitution in saposin B involving a conserved amino acidic residue and leading to the loss of the single N-glycosylation site in a patient with metachromatic leukodystrophy and normal arylsulphatase A activity

et al. 1999

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Sphingolipid activator proteins are small glycoproteins required for the degradation of sphingolipids by specific lysosomal hydrolases. Four of them, called saposins, are encoded by the prosaposin gene, the product of which is proteolytically cleaved into the four mature saposin proteins (saposins A, B, C, D). One of these, saposin B, is necessary in the hydrolysis of sulphatide by arylsulphatase A where it presents the solubilised substrate to the enzyme. As an alternative to arylsulphatase A deficiency, deficiency of saposin B causes metachromatic leukodystrophy. We identified a previously undescribed mutation (N215K) in the prosaposin gene of a patient with metachromatic leukodystrophy but with normal arylsulphatase A activity and elevated sulphatide in urine. The mutation involves a highly conserved amino acidic residue and abolishes the only N-glycosylation site of saposin B.

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Section: Introductionmentioning

confidence: 99%

An Asn > Lys substitution in saposin B involving a conserved amino acidic residue and leading to the loss of the single N-glycosylation site in a patient with metachromatic leukodystrophy and normal arylsulphatase A activity

et al. 1999

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“…Saposins (sphingolipid activator proteins) A, B, C, and D are lysosomal glycoproteins that are encoded by a single gene, termed prosaposin (14)(15)(16)(17). The saposins are essential to the optimal activity of glycosphingolipid hydrolases (18)(19)(20)(21).…”

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confidence: 99%

Gaucher disease mouse models: point mutations at the acid β-glucosidase locus combined with low-level prosaposin expression lead to disease variants

Sun

Quinn

Witte

et al. 2005

Journal of Lipid Research

100

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Gaucher disease is a common lysosomal storage disease caused by a defect of acid ␤ -glucosidase (GCase). The optimal in vitro hydrolase activity of GCase requires saposin C, an activator protein that derives from a precursor, prosaposin. To develop additional models of Gaucher disease and to test in vivo effects of saposin deficiencies, mice expressing low levels (4-45% of wild type) of prosaposin and saposins (PS-NA) were backcrossed into mice with specific point mutations (V394L/V394L or D409H/D409H) of GCase. The resultant mice were designated 4L/PS-NA and 9H/PS-NA, respectively. In contrast to PS-NA mice, the 4L/PS-NA and 9H/PS-NA mice displayed large numbers of engorged macrophages and nearly exclusive glucosylceramide (GC) accumulation in the liver, lung, spleen, thymus, and brain. Electron microscopy of the storage cells showed the characteristic tubular storage material of Gaucher cells. Compared with V394L/V394L mice, 4L/PS-NA mice that expressed 4-6% of wild-type prosaposin levels had ‫ف‬ 25-75% decreases in GCase activity and protein in liver, spleen, and fibroblasts. These results imply that reduced saposin levels increased the instability of V394L or D409H GCases and that these additional decreases led to large accumulations of GC in all tissues. These models mimic a more severe Gaucher disease phenotype and could be useful for therapeutic intervention studies. -Sun, Y., B. Quinn, D. P. Witte, and G. A. Grabowski. Gaucher disease mouse models: point mutations at the acid ␤ -glucosidase locus combined with low-level prosaposin expression lead to disease variants. J. Lipid Res. 2005. 46: 2102-2113.

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“…Five different activator proteins have been discovered to date. Four of them (sphingolipid activator proteins or saposins A-D) are proteolytically generated from a single precursor (3)(4)(5). The fifth activator, the G M2 1 activator protein (G M2 AP), is the product of a separate gene (6).…”

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confidence: 99%

Biosynthesis, Processing, and Intracellular Transport of GM2 Activator Protein in Human Epidermal Keratinocytes

Glombitza

Becker

Kaiser

et al. 1997

Journal of Biological Chemistry

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The processing, intracellular transport, and endocytosis of the G M2 activator protein (G M2 AP), an essential cofactor of ␤-hexosaminidase A for the degradation of ganglioside G M2 , was investigated in human epidermal keratinocytes. The G M2 AP precursor is synthesized as an 18-kDa peptide, which is singly glycosylated, resulting in 22-kDa high mannose and 24 -27-kDa complex glycoforms. A small portion of the 22-kDa form bears phosphomannosyl residues. About 30% of the G M2 AP precursor is secreted during 12 h after synthesis, consisting almost exclusively of complex glycoforms. In a post-Golgi compartment, the intracellular remainder is converted to a 20-kDa mature form within 24 h, bearing a heavily trimmed N-glycan on a 17-kDa backbone. Interestingly, even nonglycosylated G M2 AP is delivered to the lysosome, as shown by tunicamycin treatment and subcellular fractionation. Also, its endocytosis is independent of carbohydrate-linked signals and is even more effective for nonglycosylated G M2 AP. We conclude that a mannose-6-phosphate-independent pathway for the lysosomal delivery of G M2 AP exists in cultured human keratinocytes.

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Structure of Full-Length cDNA Coding for Sulfatide Activator, a Co-β-Glucosidase and Two Other Homologous Proteins: Two Alternate Forms of the Sulfatide Activator1

Cited by 133 publications

References 0 publications

An Asn > Lys substitution in saposin B involving a conserved amino acidic residue and leading to the loss of the single N-glycosylation site in a patient with metachromatic leukodystrophy and normal arylsulphatase A activity

An Asn > Lys substitution in saposin B involving a conserved amino acidic residue and leading to the loss of the single N-glycosylation site in a patient with metachromatic leukodystrophy and normal arylsulphatase A activity

Gaucher disease mouse models: point mutations at the acid β-glucosidase locus combined with low-level prosaposin expression lead to disease variants

Biosynthesis, Processing, and Intracellular Transport of GM2 Activator Protein in Human Epidermal Keratinocytes

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