The cryo-electron microscopy structure of γ-Secretase: towards complex assembly, substrate recognition and a catalytic mechanism.

Yanyong Kang,Karsten Melcher,H Eric Xu

doi:10.1093/nsr/nwu081

Abstract

A hallmark of AD is the presence of plaques found between neurons in the brain. These mainly consist of insoluble β-amyloid protein fragments and are thought to be cytotoxic when aggregated. This can lead to neuron death and subsequent loss of memory and perception. The β-amyloid peptide has 40~42 residues and comes from the transmembrane (TM) segment of amyloid precursor protein (APP), which has a large extracellular domain (ECD) and a small intracellular domain (ICD). APP can be processed by two different pathways. It can be cleaved by α-secretase to release the APP ECD. This cleavage blocks production of β-amyloid and reduces plaque buildup. In the second pathway, APP is first cleaved by β-secretase at the extracellular side near the TM segment, and then by γ-secretase within the TM segment. This releases β-amyloid peptides with lengths of 37–43 residues. The two major forms of β-amyloid peptides have 40 (Aβ-40) and 42 residues (Aβ-42) and contain most of the TM segment. These peptides, especially the longer Aβ-42, are hydrophobic and can easily aggregate into large oligomers.

Highlights

The most detailed structure of γ -secretase was obtained by cryo-electron microscopy (EM) at a resolution of 12 A [4]
Scheres and colleagues recently made a breakthrough by determining a 4.5 Aresolution structure of the human γ -secretase complex with cryo-EM single-particle reconstruction [5]. This achievement was made possible by two technical advances: one is the ability to obtain sufficient quality and quantity of pure γ -secretase through transient expression in mammalian cells and the other is the ability to collect and process high-quality EM data using a recently developed direct electron detector and new computational methods
The 4.5 Amap of γ -secretase reveals clear density for the NCT ectodomain, which can be modeled using a bacterial glutamate carboxypeptidase and density for the TM core of 19 TM helices arranged into a horseshoe shape (Fig. 1). This structure reveals, for the first time, the location of individual TM helices, the resolution limit prevents a detailed description of the spatial arrangement of each subunit in the complex assembly

Summary

Introduction

2. Carruthers, A, DeZutter, J and Ganguly, A et al Am J Physiol-Endocrinol Metab 2009; 297: E836– 48. The cryo-electron microscopy structure of γ -secretase: towards complex assembly, substrate recognition and a catalytic mechanism The production of β-amyloid could be blocked by inhibiting either β- or γ secretase as an effective treatment for AD.

Results

Conclusion