APH1 polar transmembrane residues regulate the assembly and activity of presenilin complexes

Raphaëlle Pardossi-Piquard, Seung Pil Yang, Soshi Kanemoto, Yongjun Gu, Fusheng Chen, Christopher Böhm, Jean Sevalle, Tong Li, Philip C. Wong, Frédéric Checler, Gerold Schmitt-Ulms, Peter St. George-Hyslop, Paul E. Fraser

Research output: Contribution to journalArticlepeer-review

Abstract

Complexes involved in the γ/ε-secretase-regulated intramembranous proteolysis of substrates such as the amyloid- β precursor protein are composed primarily of presenilin (PS1 or PS2), nicastrin, anterior pharynx defective-1 (APH1), and PEN2. The presenilin aspartyl residues form the catalytic site, and similar potentially functional polar transmembrane residues in APH1 have been identified. Substitution of charged (E84A, R87A) or polar (Q83A) residues in TM3 had no effect on complex assembly or activity. In contrast, changes to either of two highly conserved histidines (H171A, H197A) located in TM5 and TM6 negatively affected PS1 cleavage and altered binding to other secretase components, resulting in decreased amyloid generating activity. Charge replacement with His-to-Lys substitutions rescued nicastrin maturation and PS1 endoproteolysis leading to assembly of the formation of structurally normal but proteolytically inactive γ-secretase complexes. Substitution with a negatively charged side chain (His-to-Asp) or altering the structural location of the histidines also disrupted γ-secretase binding and abolished functionality of APH1. These results suggest that the conserved transmembrane histidine residues contribute to APH1 function and can affect presenilin catalytic activity.

Original languageEnglish (US)
Pages (from-to)16298-16307
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number24
DOIs
StatePublished - Jun 12 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'APH1 polar transmembrane residues regulate the assembly and activity of presenilin complexes'. Together they form a unique fingerprint.

Cite this