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

ChemMedChem. 2008 Apr;3(4):627-34. doi: 10.1002/cmdc.200700189.


Gamma-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Amyloid Precursor Protein Secretases / chemistry
  • Endopeptidases
  • Genotype
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Models, Molecular*
  • Peptide Hydrolases
  • Presenilin-1 / chemistry*


  • Membrane Proteins
  • Presenilin-1
  • APH1A protein, human
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Peptide Hydrolases