ZFIN ID: ZDB-PUB-100614-37
Transmembrane Protein 147 (TMEM147) Is a Novel Component of the Nicalin-NOMO Protein Complex
Dettmer, U., Kuhn, P.H., Abou-Ajram, C., Lichtenthaler, S.F., Krueger, M., Kremmer, E., Haass, C., and Haffner, C.
Date: 2010
Source: The Journal of biological chemistry   285(34): 26174-26181 (Journal)
Registered Authors: Haass, Christian, Haffner, Christof
Keywords: Alzheimers disease, Endoplasmic reticulum(ER), Protein assembly, Protein stability, Protein-protein interactions, APH-1, Nicastrin, Nifie14, nra-2, nra-4
MeSH Terms:
  • Amyloid Precursor Protein Secretases
  • Animals
  • Endoplasmic Reticulum
  • Humans
  • Intracellular Signaling Peptides and Proteins/metabolism*
  • Membrane Glycoproteins
  • Membrane Proteins/metabolism*
  • Multiprotein Complexes
  • Protein Binding
  • Protein Stability
  • Zebrafish
  • Zebrafish Proteins
PubMed: 20538592 Full text @ J. Biol. Chem.
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 (APP) and Notch. Nicalin and its binding partner NOMO form a complex which was shown to modulate Nodal signaling in developing zebrafish embryos. Since its experimentally determined native size (200-220 kDa) could not be satisfyingly explained by the molecular weights of Nicalin (60 kDa) and NOMO (130 kDa), we searched in affinity-purified complex preparations for additional components in the low-molecular-weight range. A ~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.