Gamma-secretase 'buckles up' to reach its destination

Date:
July 22, 2021
Source:
VIB (the Flanders Institute for Biotechnology)
Summary:
New research has 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.



FULL STORY ==========================================================================
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. The new insights are very relevant, as gamma-secretase is an important potential therapeutic target for Alzheimer's and other conditions.


==========================================================================
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. All four gamma-secretase components are transmembrane
proteins that are co-translationally inserted into the endoplasmic
reticulum (ER). 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 & Disease Research is specialized in membrane trafficking and
has a long track record of studying the gamma-secretase complex. By
combining biochemistry and high-resolution imaging, they have now
uncovered the early steps of the gamma-secretase assembly process.

"To dissect the assembly steps, we used a method developed by Randy
Schekman of UC Berkeley (who won the Noble Prize in Medicine in 2013), and
with whom we collaborated on this endeavor. This approach unveiled that
in fact dimers of two out of the four subunits are formed in the ER, in
this way preventing the premature breakdown of individual subunits," says
Wim Annaert. "These dimers only get fully assembled into gamma-secretase complexes shortly thereafter, between ER-exit and their transition to the
Golgi complex." Only fully assembled complexes are transported through
the Golgi onto their final destination in different cellular compartments.

Interestingly, the dimer assembly signature remains visible in the high- resolution structure of gamma-secretase, suggesting a 'buckle up model'
for dimer assembly: one side of the dimers act as 'buckles', while the
other side functions as the belt through interactions keeping the full
complex in place.

"This 'buckle up' mechanism could prevent the untimely processing of substrates," says Annaert. "Given the broad range of substrates and
pathways controlled by gamma-secretase -from developmental processes to
cancer and Alzheimer, the precise tuning of this assembly process allows
for further spatiotemporal regulation of gamma-secretase activity."
The insights are extremely relevant, as problems during complex
assembly may also have a significant impact on the many physiological
and pathological processes regulated by gamma-secretase.

========================================================================== Story Source: Materials provided by VIB_(the_Flanders_Institute_for_Biotechnology). Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Rosanne Wouters, Christine Michiels, Ragna Sannerud, Bertrand
Kleizen,
Katleen Dillen, Wendy Vermeire, Abril Escamilla Ayala, David
Demedts, Randy Schekman, Wim Annaert. Assembly of g-secretase
occurs through stable dimers after exit from the endoplasmic
reticulum. Journal of Cell Biology, 2021; 220 (9) DOI:
10.1083/jcb.201911104 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210722112906.htm

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