Alzheimer-linked enzyme complex ‘buckles up’ for safe trip through the cell

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A research team led by Wim Annaert (VIB-KU Leuven) discovered an early assembly of gamma secretase, a protein complex associated with many cellular processes, including the development of Alzheimer’s disease. In the first step, two dimer subcomplexes are formed. They leave the ER independently and are then assembled into a 4-subunit complex. This “buckle-up” mechanism is believed to prevent premature assembly and activity. New insights are critical because gamma secretase is an important potential therapeutic target for Alzheimer’s disease and other conditions.

Enzyme complex involved in plaque production

Gamma secretase Amyloid precursor protein, Produces a small peptide called amyloid beta, which is the main component of amyloid plaque found in the brains of people affected by Alzheimer’s disease. Gamma secretase has been studied and tested as a potential therapeutic target since its effects on the disease were discovered, but its role in the body is far broader than that of amyloid production.

Gamma secretase is a four-component complex, two of which have been found to have multiple homologues, resulting in different complexes with different intracellular distributions, providing the basis for substrate selectivity. It was. All four γ-secretase components are transmembrane proteins that are co-translated into the endoplasmic reticulum (ER). However, it was previously unclear how these four subunits would be assembled in such a stable enzyme complex.

Assembly line anatomy

The Annaert Lab at the VIB-KU Ruben Brain Disease Research Center specializes in membrane vesicle transport and has a long track record in the study of γ-secretase complexes. By combining biochemistry and high-resolution imaging, they revealed the early stages of the gamma secretase assembly process.

“We used a method developed by Randy Schekman of the University of California, Berkeley (who won the Nobel Prize in Medicine in 2013) to analyze the assembly procedure and cooperated with this effort. This approach actually resulted in 2 Two of the dimers have been revealed. Four subunits are formed in the ER, preventing premature failure of individual subsystems, “said Wim Annaert. “Shortly thereafter, these dimers are fully assembled into the gamma secretase complex during the ER exit and the transition to the Golgi complex.”

Only the fully assembled complex is transported via the Golgi to the final destination of the different intracellular compartments.

Interestingly, the features of the dimer assembly remain visible in the high resolution structure of gamma secretase, suggesting a “buckle-up model” of the dimer assembly. One side of the dimer acts as a “buckle” and the other side acts as a belt through. An interaction that keeps the complete complex in place.

“This’buckle-up’mechanism can prevent untimely processing of the board,” says Annaert. “Given the wide range of substrates and pathways controlled by gamma secretase, from development to cancer and Alzheimer’s disease, this precise coordination of the assembly process allows for further spatiotemporal regulation of gamma secretase activity. “

Insights are highly relevant, as complex assembly problems can also have a significant impact on many physiological and pathological processes regulated by. Gamma secretase..

Alzheimer’s binding protein complex at super-resolution

For more information:
Rosanne Wouters et al, γ-secretase assembly occurs via a stable dimer after exiting the endoplasmic reticulum. Journal of Cell Biology (2021). DOI: 10.1083 / jcb.201911104

Quote: The enzyme complex associated with Alzheimer’s disease “buckles” to safely pass through cells (July 22, 2021). -safe.html

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