Reconstruction of the 26S proteasome: The “regulatory particle” (in blue) detects the proteins tagged with ubiquitin and prepares them for degradation. The “core particle” (in red) breaks the proteins down into their single components. Image: Julio Ortiz/Copyright: MPI of Biochemistry |
Defective
proteins that are not disposed of by the body can cause diseases such
as Alzheimer’s or Parkinson’s. Scientists at the Max Planck Institute
(MPI) of Biochemistry recently succeeded in revealing the structure of
the cellular protein degradation machinery (26S proteasome) by combining
different methods of structural biology. The results of collaboration
with colleagues from the University of California, San Francisco and the
Swiss Federal Institute of Technology Zurich (ETH Zürich) represent an
important step forward in the investigation of the 26S proteasome. The
findings have now been published in Proceedings of the National Academy of Sciences PNAS.
At
any given point in time, cells may contain only the proteins that are
needed at exactly this moment. Otherwise, undesirable reactions can
occur which could cause cancer or other diseases. Furthermore, the
proteins have to be folded correctly to fulfill their tasks. Misfolded
proteins can clump into aggregates, and neurodegenerative diseases such
as Alzheimer’s or Parkinson’s may be the consequence. In order to
prevent this, several mechanisms in the body regulate the number of
proteins in the cell and degrade proteins if necessary.
“Cellular
waste disposal“—the 26S proteasome—plays an important role in protein
degradation. First, misfolded and potentially dangerous proteins are
tagged with molecules called ubiquitin. The 26S proteasome detects the
tagged proteins and breaks them down into small fragments, which are
then recycled. Scientists in the team of Wolfgang Baumeister, head of
the research department “Molecular Structural Biology” at the MPI of
Biochemistry, have now been able to reveal its structure.
Many puzzle pieces lead to one structure
“The
structure of the 26S proteasome changes continuously,” explained
Friedrich Förster, head of the research group “Modeling of Protein
Complexes” at the MPI of Biochemistry. “That is why until now it could
not be explained by means of traditional approaches, such as only using
X-ray crystallography. We had to combine different methods to be
successful.” Electron microscopy and mass spectrometry helped to reveal
the general structure of the 26S proteasome. X-ray crystallography
provided detailed insights into specific areas of the molecule. The
researchers then used computer software to integrate the different data
and generate an overall picture.
Based
on these results, the researchers next want to find out how the
different mechanisms of protein degradation work in detail. “We have
already developed a hypothesis of how exactly the 26S proteasome detects
tagged proteins and processes them,” said Stefan Bohn, scientist at the
MPI of Biochemistry. The complete elucidation of the 26S proteasome and
its underlying mechanisms could also be of medical importance:
“Cellular waste disposal” is a therapeutic target for cancer und
neurodegenerative diseases.
