Cloning of a cDNA encoding the human cation-dependent mannose 6-phosphate-specific receptor.

Pohlmann, R; Nagel, G. A.; Schmidt, Bernhard; Stein, Martin; Lorkowski, G; Krentler, C; Cully, J; Meyer, H. E.; Grzeschik, Karl‐Heinz; Mersmann, Günther

doi:10.1073/pnas.84.16.5575

Cited by 95 publications

(34 citation statements)

References 29 publications

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“…The first corresponds to a G, 49 nucleotides downstream of the 5' end of the longest cDNA that has been cloned (Pohlmann et al 1987), while the second is located 24 nucleotides upstream of the 5' end of the cDNA. The sequence at nucleotides -98 to -109 is the inverse homologue of nucleotides -155 to -1.67, except for one extra base (U) at position -162.…”

Section: Discussionmentioning

confidence: 99%

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Isolation and analysis of the human 46‐kDa mannose 6‐phosphate receptor gene

Klier

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Pohlmann

1991

European Journal of Biochemistry

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From a genomic library in EMBL 3, two overlapping clones for the human 46-kDa mannose 6-phosphate receptor (MPR46) were isolated, which span the entire coding sequence. The human MPR46 gene is distributed over 12 kb and is divided into seven exons (110-1573 bp). All the intron/exon borders agree with the consensus sequences of splice junctions. Exon 1 codes for a 5' untranslated sequence. The ATG initiation codon begins with the second nucleotide in exon 2. A signal sequence of 26 amino acid residues is followed by the extracytoplasmic (luminal) domain, which extends to exon 5. The transmembrane domain of the receptor spans exons 5 and 6 and the cytoplasmic domain is encoded by exons 6 and 7. The latter domain also codes for an extended 3' untranslated sequence.The transcription-initiation site was defined by primer extension. The sequence upstream of the cap site has strong promoter activity and contains structural elements characteristic of promoters found in housekeeping genes.No correlation between the genomic organization and known protein domains of the MPR46 was apparent. Moreover, the sequence of about 150 amino acids within the luminal domain of

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Section: Discussionmentioning

confidence: 99%

“…The larger of the MPR has an apparent size of 300 kDa (MPR300; Oshima et al 1988;Lobel et al 1988), and the smaller of 46 kDa (MPR46; Pohlmann et al 1987;Dahms et al 1987). The MPR46 is a transmembrane glycoprotein of 251 amino acid residues, with a larger amino-terminal luminal portion and a smaller carboxy-terminal cytosolic portion.…”

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confidence: 99%

Isolation and analysis of the human 46‐kDa mannose 6‐phosphate receptor gene

Klier

Figura

Pohlmann

1991

European Journal of Biochemistry

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“…The cDNA encoding the cytoplasmic domain of the human CD-M PR and of human L AM P-1 was obtained by PCR amplification, using L AP-M PR46 pBELC e (Pohlmann et al, 1987) as a template and oligonucleotide synthesis, respectively. The cDNA fragments were cloned into the plasmid cmv II APP695 [modified (Weidemann et al, 1989)], using new cloning sites RsaI and BspI, respectively, which have been created by PCR in the APP cDNA region encoding the last amino acid residues of the transmembrane domain just before the lysine triplet.…”

Section: Methodsmentioning

confidence: 99%

Late Compartments of Amyloid Precursor Protein Transport in SY5Y Cells Are Involved in β-Amyloid Secretion

1997

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Amyloid plaques, composed mainly of the 39-43 amino acid ␤A4 peptide, are a characteristic feature of Alzheimer's disease. Generation of ␤A4 by proteolytic processing of the amyloid precursor protein (APP) is thought to occur in a pathway that includes the activity of two as yet unknown proteases, with ␤-secretase cleaving at the N terminus and ␥-secretase releasing the C terminus of ␤A4. Inhibition studies and the finding that cell surface APP can serve as a direct precursor of ␤A4 suggest that the endosomal/lysosomal compartment is involved in the proteolysis of APP into ␤A4.In this study we targeted APP695 chimeric proteins directly into the endosomal/lysosomal compartment. This decreased the amount of released ␤A4, while the generation of the ␤A4 N terminus continued. APP695 proteins were constructed also, which carried sorting signals responsible for recycling between the trans-Golgi network (TGN) and the cell surface. These proteins were processed into secreted ␤A4 at even higher levels than wild-type APP695. Moreover, retention of APP695 proteins in the endoplasmic reticulum led to neither ␤A4 secretion nor to processing by ␤-secretase in human SH-SY5Y neuroblastoma cells.These data suggest that a ␤-cleavage activity resides in a late endosomal compartment and that a ␥-cleavage occurs in early endosomes, resulting in the generation of ␤A4 peptides with the majority ending at residue 40. Key words: Alzheimer's disease; APP processing; ␤-amyloid; chimeric proteins; endosomal/lysosomal compartment; transportA major histopathological marker of Alzheimer's disease is the presence of cerebral amyloid plaques, which are composed mainly of the insoluble 4 kDa ␤A4 peptide (Glenner and Wong, 1984;Masters et al., 1985). ␤A4 derives from the larger amyloid precursor protein (APP) by the activity of two proteases termed ␤-and ␥-secretase (Kang et al., 1987). During its transport through the constitutive secretory pathway a proportion of APP is secreted by cleavage within the ␤A4 sequence, thereby precluding the generation of ␤A4 (Weidemann et al., 1989;Esch et al., 1990).In an alternative pathway involving the endosomal/lysosomal system, APP is processed into C-terminal fragments that contain the entire ␤A4 domain (Cole et al., 1989;Golde et al., 1992;Haass et al., 1992a). Although indicating the potential importance of this part in amyloidogenic processing, these fragments also have been proposed to be intermediates of the final degradation of APP in lysosomes . However, various agents that interfere with pH gradients reduce the generation of ␤A4 drastically (Haass et al., 1992b;Shoji et al., 1992), supporting the idea that an acidic compartment is necessary for ␤A4 formation.To analyze the involvement of the endosomal/lysosomal system in the processing of APP695 into ␤A4, we created APP695 chimeras by exchanging the cytoplasmic domain of APP695 with that of the human lysosomal-associated membrane protein-1 (hLAMP-1) and the human cation-dependent mannose 6-phosphate receptor (CD-MPR). These APP hybrids were expected...

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“…Leu-192 represents the second amino acid of the predicted membrane-spanning domain of the receptor [6]. Therefore, expression of the mutated receptor cDNA was expected to result in the synthesis of soluble polypeptides which correspond to the ectoplasmic domain of MPR-46.…”

Section: Expression Of a Truncated Soluble Form Of Mpr-46mentioning

confidence: 99%

“…The EcoRI ends of P29 cDNA [6] were filled using Klenow polymerase and subcloned into the SmaI site of the vector pSVL resulting in pSVL-P29. To delete the 5'-untranslated region, pSVL-P29 was linearized with XhoI and treated with exonuclease III followed by mung bean nuclease according to the manufacturer's protocol (Stratagene, Heidelberg, Germany).…”

Section: Construction Of Expression Vectorsmentioning

confidence: 99%