TY - JOUR
T1 - Pen-2 is incorporated into the γ-secretase complex through binding to transmembrane domain 4 of presenilin 1
AU - Watanabe, Naoto
AU - Tomita, Taisuke
AU - Sato, Chihiro
AU - Kitamura, Toshio
AU - Morohashi, Yuichi
AU - Iwatsubo, Takeshi
PY - 2005/12/23
Y1 - 2005/12/23
N2 - γ-Secretase is a multimeric membrane protein complex comprised of presenilin (PS), nicastrin (Net), Aph-1, and Pen-2. It is a member of an atypical class of aspartic proteases that hydrolyzes peptide bonds within the membrane. During the biosynthetic process of the γ-secretase complex, Net and Aph-1 form a heterodimeric intermediate complex and bind to the C-terminal region of PS, serving as a stabilizing scaffold for the complex. Pen-2 is then recruited into this trimeric complex and triggers endoproteolysis of PS, conferring γ-secretase activity. Although the Pen-2 accumulation depends on PS, the binding partner of Pen-2 within the γ-secretase complex remains unknown. We reconstituted PS1 in Psen1/Psen2 deficient cells by expressing a series of PS1 mutants in which one of the N-terminal six transmembrane domains (TMDs) was swapped with those of CD4 (a type I transmembrane protein) or CLAC-P (a type II transmembrane protein). We report that the proximal two-thirds of TMD4 of PS1, including the conserved Trp-Asn-Phe sequence, are required for its interaction with Pen-2. Using a chimeric CD4 molecule harboring PS1 TMD4, we further demonstrate that the PS1 TMD4 bears a direct binding motif to Pen-2. Pen-2 may contribute to the activation of the γ-secretase complex by directly binding to the TMD4 of PS1.
AB - γ-Secretase is a multimeric membrane protein complex comprised of presenilin (PS), nicastrin (Net), Aph-1, and Pen-2. It is a member of an atypical class of aspartic proteases that hydrolyzes peptide bonds within the membrane. During the biosynthetic process of the γ-secretase complex, Net and Aph-1 form a heterodimeric intermediate complex and bind to the C-terminal region of PS, serving as a stabilizing scaffold for the complex. Pen-2 is then recruited into this trimeric complex and triggers endoproteolysis of PS, conferring γ-secretase activity. Although the Pen-2 accumulation depends on PS, the binding partner of Pen-2 within the γ-secretase complex remains unknown. We reconstituted PS1 in Psen1/Psen2 deficient cells by expressing a series of PS1 mutants in which one of the N-terminal six transmembrane domains (TMDs) was swapped with those of CD4 (a type I transmembrane protein) or CLAC-P (a type II transmembrane protein). We report that the proximal two-thirds of TMD4 of PS1, including the conserved Trp-Asn-Phe sequence, are required for its interaction with Pen-2. Using a chimeric CD4 molecule harboring PS1 TMD4, we further demonstrate that the PS1 TMD4 bears a direct binding motif to Pen-2. Pen-2 may contribute to the activation of the γ-secretase complex by directly binding to the TMD4 of PS1.
UR - http://www.scopus.com/inward/record.url?scp=29644432040&partnerID=8YFLogxK
U2 - 10.1074/jbc.M509066200
DO - 10.1074/jbc.M509066200
M3 - Article
C2 - 16234244
AN - SCOPUS:29644432040
SN - 0021-9258
VL - 280
SP - 41967
EP - 41975
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 51
ER -