Linked Life Data

12603837

Source:http://linkedlifedata.com/resource/pubmed/id/12603837

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2003-2-26
pubmed:abstractText
Abundant biochemical and genetic evidence suggests that presenilins are catalytic components of gamma-secretase, the protease responsible for generating the Alzheimer amyloid beta-protein. However, the differential localization of presenilins to early secretory compartments and gamma-secretase substrates to late secretory compartments and the plasma membrane (the "spatial paradox") argues against this view. We investigated this issue by studying the localization of nicastrin, another putative gamma-secretase component, and its association with presenilin-1 into proteolytically active complexes. Glycosidase digests revealed that nicastrin exists in multiple glycoforms and is terminally sialylated, a modification often associated with the trans-Golgi network. Trafficking of nicastrin to the trans-Golgi network was confirmed by density gradient fractionation and immunofluorescence microscopy. In presenilin-deficient cells, however, nicastrin trafficking and maturation were abnormal, as the protein was restricted to early secretory compartments and failed to be sialylated. Mature sialylated nicastrin in trans-Golgi network fractions was complexed quantitatively with N- and C-terminal fragments of presenilin-1, whereas immature nicastrin present in early secretory compartments was not. Additionally, trans-Golgi network fractions contained the gamma-secretase substrate beta-amyloid precursor protein C83 and were enriched in presenilin-dependent gamma-secretase proteolytic activity. The results resolve the apparent spatial paradox by demonstrating that presenilin-nicastrin complexes and presenilin-dependent gamma-secretase activity are co-localized to a late secretory compartment. The findings provide further evidence that presenilin-containing complexes are the gamma-secretase, and indicate that presenilins also regulate gamma-secretase assembly.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-3042
pubmed:author
pubmed:issnType
Print
pubmed:volume
84
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1143-53
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:12603837-Amyloid Precursor Protein Secretases, pubmed-meshheading:12603837-Animals, pubmed-meshheading:12603837-Aspartic Acid Endopeptidases, pubmed-meshheading:12603837-Cell Compartmentation, pubmed-meshheading:12603837-Cells, Cultured, pubmed-meshheading:12603837-Endopeptidases, pubmed-meshheading:12603837-Enzyme Activation, pubmed-meshheading:12603837-Fibroblasts, pubmed-meshheading:12603837-Glycosylation, pubmed-meshheading:12603837-Macromolecular Substances, pubmed-meshheading:12603837-Membrane Glycoproteins, pubmed-meshheading:12603837-Membrane Proteins, pubmed-meshheading:12603837-Mice, pubmed-meshheading:12603837-Presenilin-1, pubmed-meshheading:12603837-Presenilin-2, pubmed-meshheading:12603837-Protein Transport, pubmed-meshheading:12603837-Stem Cells, pubmed-meshheading:12603837-Subcellular Fractions, pubmed-meshheading:12603837-trans-Golgi Network
pubmed:year
2003
pubmed:articleTitle
Localization of presenilin-nicastrin complexes and gamma-secretase activity to the trans-Golgi network.
pubmed:affiliation
Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, JMB162, Philadelphia, PA 19104-6084, USA. siman@pharm.med.upenn.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.