Biosynthesis and molecular cloning of sulfated glycoprotein 1 secreted by rat Sertoli cells: sequence similarity with the 70-kilodalton precursor to sulfatide/GM1 activator

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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“…This fact suggests a very 20 , rat 21 , porcine 22 and chicken 23 important role for this residue in the biological activity of the protein.…”

Section: Discussionmentioning

confidence: 97%

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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“…121 By sequence matching, this protein was found to be the same as other proteins found later in various tissues, especially the brain. 122 Finally, this same protein was also identified as being associated with cellular injury, lipid transport, and apoptosis. 123 Structural characterization of clusterin has been difficult.…”

Section: Examples In Support Of the Protein Trinitymentioning

confidence: 93%

Intrinsically disordered protein

Dunker

Lawson

Brown

et al. 2001

Journal of Molecular Graphics and Modelling

2,102

2,085

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Proteins can exist in a trinity of structures: the ordered state, the molten globule and the random coil. Five examples follow which suggest that native protein structure can correspond to any of the three states (not just the ordered state) and that protein function can arise from any of the three states and their transitions. 1. In a process that likely mimics infection, fd phage converts from the ordered into the disordered molten globular state. 2. Nucleosome hyperacetylation is crucial to DNA replication and transcription; this chemical modification greatly increases the net negative charge of the nucleosome core particle. We propose that the increased charge imbalance promotes its conversion to a much less rigid form. 3. Clusterin contains an ordered domain and also a native molten globular region. The molten globular domain likely functions as a proteinaceous detergent for cell remodeling and removal of apoptotic debris. 4. In a critical signaling event, a helix in calcineurin becomes bound and surrounded by calmodulin, thereby turning on calcineurin's serine/threonine phosphatase activity.Locating the calcineurin helix within a region of disorder is essential for enabling calmodulin to surround its target upon binding. 5. Calsequestrin regulates calcium levels in the sarcoplasmic reticulum by binding about 50 ions/molecule. Disordered polyanion tails at the carboxy terminus bind many of these calcium ions, perhaps without adopting a unique structure. In addition to these examples, 16 more proteins with native disorder will be discussed. These disordered regions include molecular recognition domains, protein folding inhibitors, flexible linkers, entropic springs, entropic clocks and entropic bristles.Motivated by such examples of intrinsic disorder, we are studying the relationships between amino acid sequence and order/disorder, and from this information we are predicting intrinsic order/disorder from amino acid sequence.The sequence/structure relationships indicate that disorder is an encoded property, and the predictions strongly suggest that proteins in nature are much richer in intrinsic disorder than are those in the Protein Data Bank. Recent predictions on 29 genomes indicate that proteins from eucaryotes apparently have more intrinsic disorder than those from either bacteria or archaea, with typically > 30 % of eucaryotic proteins having disordered regions of length = 50 consecutive residues.

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“…Concordant high-level expression of its mRNA and protein has been shown in neurons of the central nervous system (CNS), particularly in Purkinje cells of the cerebellum in adult mice, and in various epithelioid and reproductive cell types in adult mice and rats [16][17][18]. The expression of prosaposin also was induced by p21, a cyclin-dependent kinase inhibitor, and serum starvation during cell-growth arrest [19].…”

Section: Introductionmentioning

confidence: 99%

“…The expression of prosaposin also was induced by p21, a cyclin-dependent kinase inhibitor, and serum starvation during cell-growth arrest [19]. Prosaposin is a major protein produced by Sertoli cells and has been termed sulphated glycoprotein 1 [18]. Post-translationally, the proteolytic processing of prosaposin and the Sp1 cluster from the longer constructs with 2400 bp of 5h-flanking DNA significantly diminished expression in the CNS.…”

Section: Introductionmentioning

confidence: 99%

Prosaposin: promoter analysis and central-nervous-system-preferential elements for expression in vivo

Sun

Jin

Witte

et al. 2000

Biochemical Journal

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The expression of prosaposin is temporally and spatially regulated at the transcriptional and post-translational levels. In itro, the mouse prosaposin promoter contains functional RORE [retinoic acid-receptor-related orphan receptor α subunit (RORα)-binding element], Sp1 and U (unknown) sites within 310 bp directly 5h to the transcription start site and additional elements within 2400 bp 5h to the transcription start site. To elucidate promoter regions important to tissue-preferential expression in i o, transgenic mice were created with 5h-flanking deletions of the prosaposin gene fused to a luciferase reporter. Nearly exclusive expression was observed in cerebrum, cerebellum and eyes of adult transgenic mice containing constructs with 234-310 bp of 5h-flanking DNA. This central nervous system (CNS) expression was due to the presence of RORE and overlapping Sp1 sites in this region. Internal deletion of RORE

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Biosynthesis and molecular cloning of sulfated glycoprotein 1 secreted by rat Sertoli cells: sequence similarity with the 70-kilodalton precursor to sulfatide/GM1 activator

Cited by 168 publications

References 40 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

Intrinsically disordered protein

Prosaposin: promoter analysis and central-nervous-system-preferential elements for expression in vivo

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