Molecular models of the interface between anterior pharynx-defective protein 1 (APH-1) and presenilin involving GxxxG motifs.

TitleMolecular models of the interface between anterior pharynx-defective protein 1 (APH-1) and presenilin involving GxxxG motifs.
Publication TypeJournal Article
Year of Publication2008
AuthorsJozwiak, Krzysztof, Krzyśko Krystiana A., Bojarski Lukasz, Gacia Magdalena, and Filipek Sławomir
JournalChemMedChem
Volume3
Issue4
Pagination627-34
Date Published2008 Apr
ISSN1860-7187
KeywordsAlzheimer Disease, Amyloid Precursor Protein Secretases, Genotype, Humans, Membrane Proteins, Models, Molecular, Peptide Hydrolases, Presenilin-1
AbstractGamma-secretase is an integral membrane protease, which is a complex of four membrane proteins. Improper functioning of gamma-secretase was found to be critical in the pathogenesis of Alzheimer's disease. Despite numerous efforts, the structure of the protease as well as its proteolytic mechanism remains poorly understood. In this work we constructed a model of interactions between two proteins forming gamma-secretase: APH-1 and presenilin. This interface is based on a highly conserved GxxxGxxxG motif in the APH-1 protein. It can form a tight contact with a small-residue AxxxAxxxG motif in presenilin. Here, four binding modes based on similar structures involving GxxxG motifs in glycophorin and aquaporin were proposed and verified. The resulting best model employs antiparallel orientations of interacting helices and is in agreement with the currently accepted topology of both proteins. This model can be used for further structural characterization of gamma-secretase and its components.
DOI10.1002/cmdc.200700189
Alternate JournalChemMedChem
PubMed ID18061918