Linked Life Data

20062056

Source:http://linkedlifedata.com/resource/pubmed/id/20062056

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2010-2-4
pubmed:abstractText
Gamma-secretase is an aspartyl protease that cleaves multiple substrates within their transmembrane domains. Gamma-secretase processes the amyloid precursor protein (APP) to generate gamma-amyloid (Agamma) peptides associated with Alzheimer's disease. Here, we show that APP possesses a substrate inhibitory domain (ASID) that negatively modulates gamma-secretase activity for Agamma production by binding to an allosteric site within the gamma-secretase complex. Alteration of this ASID by deletion or mutation, as is seen with the Flemish mutation (A21G), reduces its inhibitory potency and promotes Agamma production. Notably, peptides derived from ASID show selective inhibition of gamma-secretase activity for Agamma production over Notch1 processing. Therefore, this mode of regulation represents an unprecedented mechanism for modulating gamma-secretase, providing insight into the molecular basis of Alzheimer's disease pathogenesis and a potential strategy for the development of therapeutics.
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1545-9985
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
151-8
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
An APP inhibitory domain containing the Flemish mutation residue modulates gamma-secretase activity for Abeta production.
pubmed:affiliation
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural