Gamma Secretase

Introduction

Background

Gamma Secretase is a transmembrane aspartate protease. It catalyzes peptide bond hydrolysis of type I integral membrane proteins such as Notch, APP, and various other substrates. It recognizes and catalyzes the reaction with its substrate using 3 residue segments. These substrates generate amyloid-β (Aβ). This product is important for various neural processes, and it is well known for its Implications with Alzheimer’s disease (AD). This has made gamma secretase a popular drug target, specifically using gamma secretase (GS) inhibitors. However, due to the nature of gamma secretase having various neural functions, there are dangerous side effects when it is inhibited.

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

Though gamma secretase has multiple substrates, the substrate of main concern is called Amyloid Precursor Protein (APP). APP is composed of an N-terminal loop, a transmembrane (TM) helix, and a C-terminal β-strand. The uses lateral diffusion as a mechanism of entry into the enzyme, and once in place, the TM helix is anchored by hydrogen bonds. In order to differentiate substrates, the β-strand is often the main point of identification for the enzyme. After this, the helix undergoes unwinding and the process of catalysis can begin. TM helix anchored by hydrogen bonds Unwinding model

used for substrate recognition

Lid Complex

Lid is the first point of entry and recognition for the substrate.

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