Toward the structure of presenilin/γ-secretase and presenilin homologs.

Abstract

Presenilin is the catalytic component of the γ-secretase complex, a membrane-embedded aspartyl protease that plays a central role in biology and in the pathogenesis of Alzheimer's disease. Upon assembly with its three protein cofactors (nicastrin, Aph-1 and Pen-2), presenilin undergoes autoproteolysis into two subunits, each of which contributes one of the catalytic aspartates to the active site. A family of presenilin homologs, including signal peptide peptidase, possess proteolytic activity without the need for other protein factors, and these simpler intramembrane aspartyl proteases have given insight into the action of presenilin within the γ-secretase complex. Cellular and molecular studies support a nine-transmembrane topology for presenilins and their homologs, and small-molecule inhibitors and cysteine scanning with crosslinking have suggested certain presenilin residues and regions that contribute to substrate recognition and handling. Identification of partial complexes has also offered clues to protein-protein interactions within the γ-secretase complex. Biophysical methods have allowed 3D views of the γ-secretase complex and presenilins. Most recently, the crystal structure of a microbial presenilin homolog has confirmed a nine-transmembrane topology and intramembranous location and proximity of the two conserved and essential aspartates. The crystal structure also provides a platform for the formulation of specific hypotheses regarding substrate interaction and catalysis as well as the pathogenic mechanism of Alzheimer-causing presenilin mutations. This article is part of a Special Issue entitled: Intramembrane Proteases.

• Authors: Michael S Wolfe
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1828 Issue 12 Pg. 2886-97 (Dec 2013) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24099007 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Coenzymes
• Membrane Glycoproteins
• Membrane Proteins
• PSENEN protein, human
• Presenilin-1
• Presenilin-2
• nicastrin protein
• APH1A protein, human
• Amyloid Precursor Protein Secretases
• Endopeptidases
• Peptide Hydrolases

Topics

• Alzheimer Disease (enzymology, genetics, pathology)
• Amyloid Precursor Protein Secretases (chemistry, genetics, metabolism)
• Coenzymes (chemistry, genetics, metabolism)
• Crystallography, X-Ray
• Endopeptidases
• Humans
• Membrane Glycoproteins (chemistry, genetics, metabolism)
• Membrane Proteins (chemistry, genetics, metabolism)
• Models, Molecular
• Peptide Hydrolases (chemistry, genetics, metabolism)
• Presenilin-1 (chemistry, genetics, metabolism)
• Presenilin-2 (chemistry, genetics, metabolism)
• Protein Binding
• Protein Structure, Tertiary
• Proteolysis
• Signal Transduction
• Substrate Specificity