Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes

Yang Li ,Takeshi Iwatsubo,Taisuke Tomita,Fusheng Chen,Oksana Berezovska,Muriel Arimon,William Meadows,Seema Qamar,Ching‐Ju Tsai ,Amy Hye Won Jeon ,Lindsay A Farrer ,Christopher Böhm ,A.r Mcleod ,Bradley T Hyman ,Stephen Hsueh-Jeng Lu ,Gerold Schmitt‐Ulms ,Roger B Dodd ,Christopher M Johnson ,Paul E Fraser ,Peter St George-Hyslop

doi:10.1016/j.str.2013.09.018

Abstract

SummaryPresenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used several biophysical techniques to investigate the structure of human presenilin complexes and the effects of peptidomimetic γ-secretase inhibitors. The complexes are bilobed. The head contains nicastrin ectodomain. The membrane-embedded base has a central channel and a lateral cleft, which may represent the initial substrate docking site. Inhibitor binding induces widespread structural changes, including rotation of the head and closure of the lateral cleft. These changes block substrate access to the catalytic pocket and inhibit the enzyme. Intriguingly, peptide substrate docking has reciprocal effects on the inhibitor binding site. Similar reciprocal shifts may underlie the mechanisms of other inhibitors and of the “lateral gate” through which substrates access to the catalytic site.

Highlights

IntroductionPresenilin complexes ( known as g-secretase complexes) are composed of four core component proteins: presenilin 1(PS1; Sherrington et al, 1995) or presenilin 2 (PS2; Rogaev et al, 1995); anterior pharynx 1 (aph1; Francis et al, 2002; Goutte et al, 2002); presenilin enhancer 2 (pen2; Francis et al, 2002); and nicastrin (Yu et al, 2000) (Figure 1A)
Presenilin complexes are composed of four core component proteins: presenilin 1(PS1; Sherrington et al, 1995) or presenilin 2 (PS2; Rogaev et al, 1995); anterior pharynx 1; presenilin enhancer 2; and nicastrin (Yu et al, 2000) (Figure 1A)
Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers

Summary

Introduction

Presenilin complexes ( known as g-secretase complexes) are composed of four core component proteins: presenilin 1(PS1; Sherrington et al, 1995) or presenilin 2 (PS2; Rogaev et al, 1995); anterior pharynx 1 (aph1; Francis et al, 2002; Goutte et al, 2002); presenilin enhancer 2 (pen2; Francis et al, 2002); and nicastrin (Yu et al, 2000) (Figure 1A). The mature presenilin complexes perform the intramembranous endoproteolysis of several biologically important Type I transmembrane (TM) proteins, including Notch, p75, and the amyloid precursor protein (APP; Haass and Selkoe, 2007). This cleavage is catalyzed by two aspartate residues that are thought to be located in a hydrophilic pocket surrounded by the TM domains of the core complex proteins—one located on TM6 in the PS1-NTF, the other on TM7 in the PS1-CTF (Wolfe et al, 1999). It has been speculated that substrates may gain access to the active site of the presenilin aspartyl protease family by a ‘‘lateral

Results

Discussion

Conclusion