Molecular insights into the ubiquitin system and its association with human diseases

20 October 2013

Ribbon representation of the atomic structure of ubiquitin.

Image: Ribbon representation of the atomic structure of ubiquitin.

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.

 

  • A team from the Medical Research Council's National Institute for Medical Research has made an important step forward in understanding how a small protein called ubiquitin is involved in many human diseases.
  • It's hoped that the work may lead to the development of new clinical treatments.
  • Ubiquitin is attached to other proteins, often in the form of long chains (called poly-ubiquitin chains), to signal their fate - such as to be destroyed or to become activated. The way in which these chains are linked together decides the specific fate of the protein they are attached to.