The Nicastrin-like protein Nicalin regulates assembly and stability of the Nicalin-nodal modulator (NOMO) membrane protein complex.
The assembly of the gamma-secretase complex, an Alzheimer disease-related protease required for beta-amyloid generation, is tightly regulated and predominantly limited by the stoichiometrical availability of its components. We have identified a novel endoplasmic reticulum-located protein complex that is regulated in a similar fashion. It contains the recently identified Nodal signaling antagonists Nicalin (a distant homolog of the gamma-secretase component Nicastrin) and NOMO (Nodal modulator). Using an RNA interference approach, we found that Nicalin and NOMO became unstable in the absence of the respective binding partner, suggesting that complex formation has a stabilizing effect. Overexpression of Nicalin resulted in an increase in NOMO, whereas endogenous Nicalin was reduced below the detection limit. Both effects were shown to occur at a post-transcriptional level. Thus, NOMO is most likely produced in excess amounts and either stabilized by Nicalin or rapidly degraded. In contrast, Nicalin levels are limited independently of NOMO. We, therefore, propose that Nicalin controls the assembly and stability of the Nicalin-NOMO complex.
Haffner
Christof
C
Center of Integrated Protein Science and the Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig-Maximilians-University, D-80336 Munich, Germany. chaffner@med.uni-muenchen.de
Dettmer
Ulf
U
Weiler
Timotheus
T
Haass
Christian
C
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic
D016229:Amyloid beta-Peptides; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C520019:NCLN protein, human; C501109:NOMO3 protein, human; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases