title: The biochemical and genetic odyssey to the function of a nicastrin-like protein.
abstract: Gamma-secretase is a high-molecular-weight protein complex required for the proteolytic processing of various transmembrane proteins including the Alzheimer's disease-associated amyloid precursor protein and the signaling receptor Notch. One of the gamma-secretase complex components is the type I transmembrane protein nicastrin. Here we review the odyssey to a cyclopic fish, which at the end allowed the functional analysis of nicalin, a novel member of the nicastrin protein family. This 60-kDa protein is part of a previously unknown membrane protein complex unrelated to gamma-secretase and binds to Nomo (Nodal modulator, previously known as pM5), a novel 130-kDa transmembrane protein. Both proteins are highly conserved in metazoans and show almost identical tissue distribution in humans. Functional studies in zebrafish embryos and cultured human cells revealed that nicalin and Nomo collaborate to antagonize the Nodal/TGFbeta signaling pathway. Thus, nicastrin and nicalin are both associated with protein complexes involved in cell fate decisions during early embryonic development.
authors.affiliation: Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Munich, Germany. chaffner@med.uni-muenchen.de
authors.forename: Christof
authors.initials: C
authors.lastname: Haffner
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: D008562:Membrane Glycoproteins; D029961:Zebrafish Proteins; C501106:ncln protein, zebrafish; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human