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Article: Nicastrin binds to membrane-tethered Notch

TitleNicastrin binds to membrane-tethered Notch
Authors
Issue Date2001
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/naturecellbiology
Citation
Nature Cell Biology, 2001, v. 3 n. 8, p. 751-754 How to Cite?
AbstractThe presenilins 1,2 and nicastrin 3, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the β-amyloid precursor protein (βAPP) 3-7 and Notch 8-11 in their transmembrane domains. The former process (termed γ-secretase cleavage) generates amyloid β-peptide (Aβ), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length βAPP and the substrates of γ-secretase (C99- and C83-βAPP fragments), and modulates the activity of γ-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype 3,12, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate γ-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and βAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and βAPP pathways do not significantly compete with each other.
Persistent Identifierhttp://hdl.handle.net/10722/134746
ISSN
2015 Impact Factor: 18.699
2015 SCImago Journal Rankings: 14.131
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChen, Fen_HK
dc.contributor.authorYu, Gen_HK
dc.contributor.authorArawaka, Sen_HK
dc.contributor.authorNishimura, Men_HK
dc.contributor.authorKawarai, Ten_HK
dc.contributor.authorYu, Hen_HK
dc.contributor.authorTandon, Aen_HK
dc.contributor.authorSupala, Aen_HK
dc.contributor.authorSong, YQen_HK
dc.contributor.authorRogaeva, Een_HK
dc.contributor.authorMilman, Pen_HK
dc.contributor.authorSato, Cen_HK
dc.contributor.authorYu, Cen_HK
dc.contributor.authorJanus, Cen_HK
dc.contributor.authorLee, Jen_HK
dc.contributor.authorSong, Len_HK
dc.contributor.authorZhang, Len_HK
dc.contributor.authorFraser, PEen_HK
dc.contributor.authorSt GeorgeHyslop, PHen_HK
dc.date.accessioned2011-07-14T07:02:33Z-
dc.date.available2011-07-14T07:02:33Z-
dc.date.issued2001en_HK
dc.identifier.citationNature Cell Biology, 2001, v. 3 n. 8, p. 751-754en_HK
dc.identifier.issn1465-7392en_HK
dc.identifier.urihttp://hdl.handle.net/10722/134746-
dc.description.abstractThe presenilins 1,2 and nicastrin 3, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the β-amyloid precursor protein (βAPP) 3-7 and Notch 8-11 in their transmembrane domains. The former process (termed γ-secretase cleavage) generates amyloid β-peptide (Aβ), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length βAPP and the substrates of γ-secretase (C99- and C83-βAPP fragments), and modulates the activity of γ-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype 3,12, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate γ-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and βAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and βAPP pathways do not significantly compete with each other.en_HK
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/naturecellbiologyen_HK
dc.relation.ispartofNature Cell Biologyen_HK
dc.subject.meshAlzheimer Disease/metabolismen_US
dc.subject.meshAmyloid Precursor Protein Secretasesen_US
dc.subject.meshAmyloid beta-Peptides/biosynthesis/geneticsen_US
dc.subject.meshAmyloid beta-Protein Precursor/genetics/*metabolismen_US
dc.subject.meshAspartic Acid Endopeptidasesen_US
dc.subject.meshBinding Sites/physiologyen_US
dc.subject.meshCell Membrane/*metabolism/ultrastructureen_US
dc.subject.meshCells, Cultured/cytology/metabolismen_US
dc.subject.meshEndopeptidases/genetics/metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshMembrane Glycoproteins/genetics/*metabolismen_US
dc.subject.meshMembrane Proteins/genetics/*metabolismen_US
dc.subject.meshMutation/physiologyen_US
dc.subject.meshProtein Structure, Tertiary/physiologyen_US
dc.subject.meshReceptors, Notchen_US
dc.subject.meshSignal Transduction/*physiologyen_US
dc.subject.meshTransfectionen_US
dc.titleNicastrin binds to membrane-tethered Notchen_HK
dc.typeArticleen_HK
dc.identifier.emailSong, YQ:songy@hkucc.hku.hken_HK
dc.identifier.authoritySong, YQ=rp00488en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/35087069en_HK
dc.identifier.pmid11483961-
dc.identifier.scopuseid_2-s2.0-0034896955en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0034896955&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume3en_HK
dc.identifier.issue8en_HK
dc.identifier.spage751en_HK
dc.identifier.epage754en_HK
dc.identifier.isiWOS:000170393200021-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridChen, F=7404907428en_HK
dc.identifier.scopusauthoridYu, G=35370376900en_HK
dc.identifier.scopusauthoridArawaka, S=6602984633en_HK
dc.identifier.scopusauthoridNishimura, M=7403650959en_HK
dc.identifier.scopusauthoridKawarai, T=7003632751en_HK
dc.identifier.scopusauthoridYu, H=23092412900en_HK
dc.identifier.scopusauthoridTandon, A=7103281816en_HK
dc.identifier.scopusauthoridSupala, A=6602797868en_HK
dc.identifier.scopusauthoridSong, YQ=7404921212en_HK
dc.identifier.scopusauthoridRogaeva, E=35372614800en_HK
dc.identifier.scopusauthoridMilman, P=7004252433en_HK
dc.identifier.scopusauthoridSato, C=7201887342en_HK
dc.identifier.scopusauthoridYu, C=7404977928en_HK
dc.identifier.scopusauthoridJanus, C=7005274261en_HK
dc.identifier.scopusauthoridLee, J=36152832100en_HK
dc.identifier.scopusauthoridSong, L=7402537737en_HK
dc.identifier.scopusauthoridZhang, L=9280030900en_HK
dc.identifier.scopusauthoridFraser, PE=35408135200en_HK
dc.identifier.scopusauthoridSt GeorgeHyslop, PH=7005637468en_HK

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