Gamma Secretase

Introduction

Background

Gamma Secretase is a transmembrane aspartate protease Catalyzes peptide bond hydrolysis of type I integral membrane proteins Such as Notch, APP, and various other substrates 3 residue segments; allow binding and cleavage Generates amyloid-β (Aβ) Important for neural processes Implications with Alzheimer’s disease (AD) Drug target GS inhibitors Dangerous side effects

Overall Structure

20 transmembrane components (TMs) 4 subunits Nicastran (NCT),Anterior pharynx-defective 1 (APH-1), Presenilin (PS1), Presenilin enhancer 2 (PEN-2), and4 phosphatidylcholines stabilize structure (interface between PS1 and PEN-2; APH-1 and PS1; APH-1 and NCT)

Figure 1

5A63 Article

practice

Structural highlights

Substrate Structure

Made of an N-terminal loop, a transmembrane helix, and a C-terminal β-strand Lateral diffusion to enter enzyme TM helix anchored by hydrogen bonds Unwinding model β-strand used for substrate recognition

Lid Complex

Active Site

Relevance

APP build up leads to Amyloid plaques in brain Inhibition of γ-secretase could be potential AD treatment Location of majority of mutations Over 200 mutations that cause AD AD mutations heavily target interface between PS1 and APP Important to look at differences between substrates