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Dettmer, U.* ; Kuhn, P.H.* ; Abou-Ajram, C.* ; Lichtenthaler, S.F.* ; Krüger, M.* ; Kremmer, E. ; Haass, C.* ; Haffner, C.*

Transmembrane protein 147 (TMEM147) is a novel component of the Nicalin-NOMO protein complex.

J. Biol. Chem. 285, 26174-26181 (2010)
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Nicastrin and its relative Nicalin (Nicastrin-like protein) are both members of larger protein complexes, namely gamma-secretase and the Nicalin-NOMO (Nodal modulator) complex. The gamma-secretase complex, which contains Presenilin, APH-1, and PEN-2 in addition to Nicastrin, catalyzes the proteolytic cleavage of the transmembrane domain of various proteins including the beta-amyloid precursor protein and Notch. Nicalin and its binding partner NOMO form a complex that was shown to modulate Nodal signaling in developing zebrafish embryos. Because its experimentally determined native size (200-220 kDa) could not be satisfyingly explained by the molecular masses of Nicalin (60 kDa) and NOMO (130 kDa), we searched in affinity-purified complex preparations for additional components in the low molecular mass range. A approximately 22-kDa protein was isolated and identified by mass spectrometry as transmembrane protein 147 (TMEM147), a novel, highly conserved membrane protein with a putative topology similar to APH-1. Like Nicalin and NOMO, it localizes to the endoplasmic reticulum and is expressed during early zebrafish development. Overexpression and knockdown experiments in cultured cells demonstrate a close relationship between the three proteins and suggest that they are components of the same complex. We present evidence that, similar to gamma-secretase, its assembly is hierarchical starting with the formation of a Nicalin-NOMO intermediate. Nicalin appears to represent the limiting factor regulating the assembly rate by stabilizing the other two components. We conclude that TMEM147 is a novel core component of the Nicalin-NOMO complex, further emphasizing its similarity with gamma-secretase.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Gamma-secretase complex; Amyloid beta-peptide; Caenorhabditis-elegans; Intramembrane proteolysis; Signaling pathway; Nicastrin; Presenilin; APH-1; Receptor; Notch
Language english
Publication Year 2010
HGF-reported in Year 2010
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Quellenangaben Volume: 285, Issue: 34, Pages: 26174-26181 Article Number: , Supplement: ,
Publisher American Society for Biochemistry and Molecular Biology
Reviewing status Peer reviewed
PSP Element(s) G-501700-003
PubMed ID 20538592
Scopus ID 77956198869
Erfassungsdatum 2010-10-14