A protein called ubiquitin plays a fundamental role in the
regulation of cellular functions, and not surprisingly mistakes in
the ubiquitin system have been implicated in a number of human
diseases, including cancer, neurodegenerative conditions such as
Parkinson's disease and immune disorders such as asthma and
rheumatoid arthritis.
A new study has uncovered important molecular insights into
exactly how the ubiquitin system works - furthering scientists'
understanding of what can go wrong and potentially opening up a new
avenue for drug development.
The research was led by Katrin Rittinger of the Medical Research
Council's National Institute for Medical Research (NIMR; now
part of the Francis Crick Institute). She explained:
"Ubiquitin is a small protein that can be attached to other
proteins, often in the form of chains of many ubiquitin molecules.
The way in which the ubiquitin molecules are linked to one another
is crucial in determining the fate of the protein that has been
'tagged' and can, for example, signal that the protein needs to be
destroyed or, alternatively, become activated."
Dr Rittinger's team at NIMR worked with colleagues from the
Goethe University, School of Medicine in Frankfurt, Germany. They
used X-ray crystallography to determine the three-dimensional
structure of a - ubiquitin protein bound to the enzyme responsible
for making ubiquitin chains (known as a complex). This allowed them
to visulise the atomic structure of the complex. Next the
researchers designed mutant proteins that enabled them to use
biochemical and cell biological methods to investigate precisely
how ubiquitin chains are made.
They discovered important insights into how enzymes called E3
ubiquitin ligases are able to make specific types of ubiquitin
chains. The fate of a tagged protein is precisely determined
by the addition of one of these specific ubiquitin chains.
Linear ubiquitin chains, the focus of this study, are particularly
important for the correct regulation of immune and inflammatory
responses.
Dr Rittinger said: "Alterations of the ubiquitination system
have been associated with a variety of diseases including cancer,
neurodegeneration and immune disorders.
"An understanding of the molecular mechanisms underlying
ubiquitination may suggest ways to interfere with abnormal cell
processes - and may even lead to the development of new treatments
for a number of diseases."
The paper, Structural basis for ligase-specific conjugation of linear
ubiquitin chains by HOIP, is published
in Nature.