Sumary of Gamma-secretase ‘buckles up’ to reach its destination:
- A research team led by Wim Annaert (VIB-KU Leuven) uncovered the early assembly of gamma-secretase, a protein complex linked to numerous cellular processes including the development of Alzheimer’s disease.
- In a first step, two dimeric subcomplexes are formed, which independently exit the ER and only afterwards assemble into a four-subunit complex.
- This ‘buckle up’ mechanism is thought to prevent premature assembly and activity.
- An enzyme complex involved in plaque production Gamma-secretase is best known as the enzyme that cleaves the amyloid precursor protein, generating a small peptide called amyloid beta, the main constituent of the plaques found in the brains of people affected by Alzheimer’s disease.
- Ever since the discovery of its implication in disease, gamma-secretase has been studied and tested as a potential therapeutic target, but its role in the body is much broader than producing amyloid.
- We now know that gamma-secretase is a complex made up of four components, two of which have multiple homologues, resulting in variety of complexes with distinct subcellular distributions, providing a basis for substrate selectivity.
- But how these four subunits get assembled in such stable enzyme complexes remained unknown until now.
- Dissecting the assembly line The Annaert lab at the VIB-KU Leuven Center for Brain &