Abstract
The 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 751-754 |
| Number of pages | 4 |
| Journal | Nature Cell Biology |
| Volume | 3 |
| Issue number | 8 |
| DOIs | |
| State | Published - 2001 |
Fingerprint
ASJC Scopus subject areas
- Cell Biology
Cite this
Nicastrin binds to membrane-tethered Notch. / Chen, Fusheng; Yu, Gang; Arawaka, Shigeki; Nishimura, Masaki; Kawarai, Toshitaka; Yu, Haung; Tandon, Anurag; Supala, Agnes; Song, You Qiang; Rogaeva, Ekaterina; Milman, Paul; Sato, Christine; Yu, Cong; Janus, Christopher; Lee, Julie; Song, Lixin; Zhang, Lili; Fraser, Paul E.; St George-Hyslop, P. H.
In: Nature Cell Biology, Vol. 3, No. 8, 2001, p. 751-754.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Nicastrin binds to membrane-tethered Notch
AU - Chen, Fusheng
AU - Yu, Gang
AU - Arawaka, Shigeki
AU - Nishimura, Masaki
AU - Kawarai, Toshitaka
AU - Yu, Haung
AU - Tandon, Anurag
AU - Supala, Agnes
AU - Song, You Qiang
AU - Rogaeva, Ekaterina
AU - Milman, Paul
AU - Sato, Christine
AU - Yu, Cong
AU - Janus, Christopher
AU - Lee, Julie
AU - Song, Lixin
AU - Zhang, Lili
AU - Fraser, Paul E.
AU - St George-Hyslop, P. H.
PY - 2001
Y1 - 2001
N2 - The 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.
AB - The 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.
UR - http://www.scopus.com/inward/record.url?scp=0034896955&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034896955&partnerID=8YFLogxK
U2 - 10.1038/35087069
DO - 10.1038/35087069
M3 - Article
VL - 3
SP - 751
EP - 754
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 8
ER -