A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse

Matsuda, Junko; Vanier, Marie T.; Saito, Yuko; Tohyama, Jun; Suzuki, Kinuko; Suzuki, Kazuyuki

doi:10.1093/hmg/10.11.1191

Cited by 143 publications

(140 citation statements)

References 36 publications

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“…Saposin A is required for galactosylceramide degradation by galactosylceramide-␤-galactosidase. Mice lacking saposin A accumulate galactosylceramide and suffer from a form of Krabbe's disease (20). Saposin B facilitates the degradation of a variety of lipids, including sulfatide by arylsulfatase A and globotriaosylceramide and digalactosylceramide by ␣-galactosidase A.…”

mentioning

confidence: 99%

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Yuan

Tsang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

101

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CD1d molecules bind lipid antigens in the endocytic pathway, and access to the pathway is important for the development of CD1d-restricted natural killer T (NKT) cells. Saposins, derived from a common precursor, prosaposin, are small, heat-stable lysosomal glycoproteins required for lysosomal degradation of sphingolipids. Expression of prosaposin is required for efficient lipid binding and recognition of human CD1d molecules by NKT cells. Despite high sequence homology among the four saposins, they have different specificities for lipid substrates and different mechanisms of action. To determine the saposins involved in promoting lipid binding to CD1d, we expressed prosaposin deletion mutants lacking individual saposins in prosaposin-negative, CD1d-positive cells. No individual saposin proved to be absolutely essential, but the absence of saposin B resulted in the lowest recognition of α-galactosylceramide by NKT cells. When recombinant exogenous saposins were added to the prosaposin-negative cells, saposin B was the most efficient in restoring CD1d recognition. Saposin B was also the most efficient in mediating α-galactosylceramide binding to recombinant plate-bound CD1d and facilitating NKT cell activation. Saposin B could also mediate lipid binding to soluble CD1d molecules in a T cell-independent assay. The optimal pH for saposin B-mediated lipid binding to CD1d, pH 6, is higher than that of lysosomes, suggesting that saposin B may facilitate lipid binding to CD1d molecules throughout the endocytic pathway.

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mentioning

confidence: 99%

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Yuan

Tsang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

101

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“…The saposin group of enzymes, which include saposin A, B, C and D derived from prosaposin by proteolytic cleavage, plays an indispensable role in activating the lysosomatic enzymes and preparing glycosphingolipidic substrates. [28][29][30] Two mechanisms of action appear to be involved in sphingolipid activator function. Some activators (e.g., saposin B) mobilize glycosphingolipids by loosening the sphingolipid's ceramide moiety within the membrane, thereby making the sphingolipid's glycosyl groups more accessible to sphingolipid hydrolases.…”

Section: Galc Gene Methylationmentioning

confidence: 99%

“…This finding has been used to establish a new mouse model in order to study CGD. 28 However, there is currently no data available regarding saposin gene transcription, translation or enzyme activity changes in cancer cells.…”

Section: Galc Gene Methylationmentioning

confidence: 99%

Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

Beier

Görögh

2005

Intl Journal of Cancer

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Galactosylcerebroside is known to be overexpressed upon the cellular surface of a variety of cancers. In squamous cell carcinomas of the head and neck, one explanation for galactosylcerebroside accumulation has been identified as a transcriptional repression of the galactocerebrosidase gene. Galactocerebrosidase is the enzyme responsible for degrading galactosylcerebroside to ceramide. Ceramide is an important apoptosis activator, whereas galactosylcerebroside functions as an inhibitor. A shift of the ceramide metabolism balance in favor of glycosylated forms has been identified as a mechanism of drug resistance for several antineoplastic agents. Our review elaborates on possible explanations for galactocerebrosidase suppression and on other explanations for increased glycosphingolipid concentration within cancer cell membranes. Furthermore, conjecturable influences of a repressed galactocerebrosidase expression on tumor biology are to be explained. The inhibiting transcription factors YY1 and AP2 have been identified as potential galactocerebrosidase gene suppressors. The resulting accumulation of galactosylcerebroside promotes a reduction of cellular adhesion and inhibits apoptosis, leading to increased cellular growth, migration and prolonged cell survival contributing to carcinogenesis. ' 2005 Wiley-Liss, Inc.

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“…Examples of SAPLIP functions include roles in exohydrolase degradation of sphingolipids in the lysosome (saposins) (17), antimicrobial activity (granulysin and NK-lysin) (18), tumor lysis (NK-lysin) (19), pulmonary surfactant surface tension regulation (surfactant protein B) (20), and bacterial/eukaryotic cell lysis (amoebapores) (21).…”

mentioning

confidence: 99%

Structure and Mechanism of the Saposin-like Domain of a Plant Aspartic Protease

Bryksa

Bhaumik

Magracheva

et al. 2011

Journal of Biological Chemistry

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Many plant aspartic proteases contain an additional sequence of ϳ100 amino acids termed the plant-specific insert, which is involved in host defense and vacuolar targeting. Similar to all saposin-like proteins, the plant-specific insert functions via protein-membrane interactions; however, the structural basis for such interactions has not been studied, and the nature of plantspecific insert-mediated membrane disruption has not been characterized. In the present study, the crystal structure of the saposin-like domain of potato aspartic protease was resolved at a resolution of 1.9 Å , revealing an open V-shaped configuration similar to the open structure of human saposin C. Notably, vesicle disruption activity followed Michaelis-Menten-like kinetics, a finding not previously reported for saposin-like proteins including plant-specific inserts. Circular dichroism data suggested that secondary structure was pH-dependent in a fashion similar to influenza A hemagglutinin fusion peptide. Membrane effects characterized by atomic force microscopy and light scattering indicated bilayer solubilization as well as fusogenic activity. Taken together, the present study is the first report to elucidate the membrane interaction mechanism of plant saposin-like domains whereby pH-dependent membrane interactions resulted in bilayer fusogenic activity that probably arose from a viral type pH-dependent helix-kink-helix motif at the plant-specific insert N terminus. Aspartic proteases (APs)2 are characterized by a common bilobal tertiary structure containing two catalytic aspartic acid residues (Asp 32 and Asp 215 in pepsin) within an active site cleft(1, 2). They are found in all higher organisms, and their respective roles are well established, although structural and functional characteristics of APs in plants are least understood. Of practical interest among plant APs are their roles in plant pathogen resistance (3) as well as in senescence and postharvest physiology (4, 5). Plant APs share the common AP bilobal structure; however, some contain an additional sequence of ϳ100 residues inserted within the C-terminal primary structure. These additional amino acids unique to plant APs (6 -8) create an extra domain protruding from the canonical AP molecule (9 -11). This structural oddity among APs is called the plantspecific insert (PSI), also known as the plant-specific sequence, which belongs to the saposin-like protein (SAPLIP) family (12, 13). Plant APs are found in either monomeric or heterodimeric forms (9, 14); the latter result from post-translational proteolysis, which includes the removal of part or all of the PSI, whereas the PSI is retained in monomeric plant APs (6,8).In general, members of the SAPLIP family have various physiological functions, all of which entail membrane interaction (14 -16) manifested in three principal ways: membrane binding, membrane perturbation without permeabilization, and membrane permeabilization (15). Examples of SAPLIP functions include roles in exohydrolase degradation of sphingolipids in the...

show abstract

A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse

Cited by 143 publications

References 36 publications

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

Structure and Mechanism of the Saposin-like Domain of a Plant Aspartic Protease

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