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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
42
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pubmed:dateCreated |
2009-10-12
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pubmed:abstractText |
TMP21 has been shown to be associated with the gamma-secretase complex and can specifically regulate gamma-cleavage without affecting epsilon-mediated proteolysis. To explore the basis of this activity, TMP21 modulation of gamma-secretase activity was investigated independent of epsilon-cleavage using an amyloid-beta precursor proteinepsilon (APPepsilon) construct which lacks the amyloid intracellular domain domain. The APPepsilon construct behaves similarly to the full-length precursor protein with respect to alpha- and beta-cleavages and is able to undergo normal gamma-processing. Co-expression of APPepsilon and TMP21 resulted in the accumulation of membrane-embedded higher molecular weight Abeta-positive fragments, consistent with an inhibition of gamma-secretase cleavage. The APPepsilon system was used to examine the functional domains of TMP21 through the investigation of a series of TMP21-p24a chimera proteins. It was found that chimeras containing the transmembrane domain bound to the gamma-secretase complex and could decrease gamma-secretase proteolytic processing. This was confirmed though investigation of a synthetic peptide corresponding to the TMP21 transmembrane helix. The isolated TMP21 TM peptide but not the homologous p24a domain was able to reduce Abeta production in a dose-dependent fashion. These observations suggest that the TMP21 transmembrane domain promotes its association with the presenilin complex that results in decreased gamma-cleavage activity.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/19710022-10206644,
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1083-351X
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
16
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pubmed:volume |
284
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
28634-41
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:19710022-Amyloid Precursor Protein Secretases,
pubmed-meshheading:19710022-Amyloid beta-Peptides,
pubmed-meshheading:19710022-Cell Line,
pubmed-meshheading:19710022-Cell Membrane,
pubmed-meshheading:19710022-Cell-Free System,
pubmed-meshheading:19710022-Electrophoresis, Polyacrylamide Gel,
pubmed-meshheading:19710022-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:19710022-Genes, Reporter,
pubmed-meshheading:19710022-Humans,
pubmed-meshheading:19710022-Lysine,
pubmed-meshheading:19710022-Membrane Proteins,
pubmed-meshheading:19710022-Mutagenesis,
pubmed-meshheading:19710022-Peptides,
pubmed-meshheading:19710022-Protein Structure, Tertiary,
pubmed-meshheading:19710022-Recombinant Fusion Proteins
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pubmed:year |
2009
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pubmed:articleTitle |
TMP21 transmembrane domain regulates gamma-secretase cleavage.
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pubmed:affiliation |
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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