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PEN-2 enhances gamma-cleavage after presenilin heterodimer formation.
J Neurochem. 2004 Sep; 90(6):1402-13.JN

Abstract

The presenilin (PS) complex, including PS, nicastrin, APH-1 and PEN-2, is essential for gamma-secretase activity, which is required for amyloid beta-protein (Abeta) generation. However, the precise individual roles of the three cofactors in the PS complex in Abeta generation remain to be clarified. Here, to distinguish the roles of PS cofactors in gamma-secretase activity from those in PS endoproteolysis, we investigated their roles in the gamma-secretase activity reconstituted by the coexpression of PS N- and C-terminal fragments (NTF and CTF) in PS-null cells. We demonstrate that the coexpression of PS1 NTF and CTF forms the heterodimer and restores Abeta generation in PS-null cells. The generation of Abeta was saturable at a certain expression level of PS1 NTF/CTF, while the overexpression of PEN-2 alone resulted in a further increase in Abeta generation. Although PEN-2 did not enhance PS1 NTF/CTF heterodimer formation, PEN-2 expression reduced the IC50 of a specific gamma-secretase inhibitor, a transition state analogue, for Abeta generation, suggesting that PEN-2 expression enhances the affinity or the accessibility of the substrate to the catalytic site. Thus, our results strongly suggest that PEN-2 is not only an essential component of the gamma-secretase complex but also an enhancer of gamma-cleavage after PS heterodimer formation.

Authors+Show Affiliations

Department of Dementia Research, National Institute for Longevity Sciences, Morioka, Obu, Aichi, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15341524

Citation

Shiraishi, Hirohisa, et al. "PEN-2 Enhances Gamma-cleavage After Presenilin Heterodimer Formation." Journal of Neurochemistry, vol. 90, no. 6, 2004, pp. 1402-13.
Shiraishi H, Sai X, Wang HQ, et al. PEN-2 enhances gamma-cleavage after presenilin heterodimer formation. J Neurochem. 2004;90(6):1402-13.
Shiraishi, H., Sai, X., Wang, H. Q., Maeda, Y., Kurono, Y., Nishimura, M., Yanagisawa, K., & Komano, H. (2004). PEN-2 enhances gamma-cleavage after presenilin heterodimer formation. Journal of Neurochemistry, 90(6), 1402-13.
Shiraishi H, et al. PEN-2 Enhances Gamma-cleavage After Presenilin Heterodimer Formation. J Neurochem. 2004;90(6):1402-13. PubMed PMID: 15341524.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PEN-2 enhances gamma-cleavage after presenilin heterodimer formation. AU - Shiraishi,Hirohisa, AU - Sai,Xiaorei, AU - Wang,Hua-Qin, AU - Maeda,Yasuhiro, AU - Kurono,Yukihisa, AU - Nishimura,Masaki, AU - Yanagisawa,Katsuhiko, AU - Komano,Hiroto, PY - 2004/9/3/pubmed PY - 2004/10/28/medline PY - 2004/9/3/entrez SP - 1402 EP - 13 JF - Journal of neurochemistry JO - J Neurochem VL - 90 IS - 6 N2 - The presenilin (PS) complex, including PS, nicastrin, APH-1 and PEN-2, is essential for gamma-secretase activity, which is required for amyloid beta-protein (Abeta) generation. However, the precise individual roles of the three cofactors in the PS complex in Abeta generation remain to be clarified. Here, to distinguish the roles of PS cofactors in gamma-secretase activity from those in PS endoproteolysis, we investigated their roles in the gamma-secretase activity reconstituted by the coexpression of PS N- and C-terminal fragments (NTF and CTF) in PS-null cells. We demonstrate that the coexpression of PS1 NTF and CTF forms the heterodimer and restores Abeta generation in PS-null cells. The generation of Abeta was saturable at a certain expression level of PS1 NTF/CTF, while the overexpression of PEN-2 alone resulted in a further increase in Abeta generation. Although PEN-2 did not enhance PS1 NTF/CTF heterodimer formation, PEN-2 expression reduced the IC50 of a specific gamma-secretase inhibitor, a transition state analogue, for Abeta generation, suggesting that PEN-2 expression enhances the affinity or the accessibility of the substrate to the catalytic site. Thus, our results strongly suggest that PEN-2 is not only an essential component of the gamma-secretase complex but also an enhancer of gamma-cleavage after PS heterodimer formation. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/15341524/PEN_2_enhances_gamma_cleavage_after_presenilin_heterodimer_formation_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3042&date=2004&volume=90&issue=6&spage=1402 DB - PRIME DP - Unbound Medicine ER -