Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Ubiquitous and influential

14.02.2017

Scientists at the University of Würzburg have generated new insights into the intricate molecular underpinnings of ubiquitin signaling. Their results may provide new avenues for cancer therapy.

The small protein ubiquitin regulates a plethora of physiological and pathophysiological processes in the human body. It lives up to its name quite literally by being ubiquitous, both in terms of its abundance and its far-reaching regulatory impact.


Crystal structure of the ubiquitin ligase HUWE1 in the newly discovered inactive state. The region that mediates dimer formation is highlighted (orange, dark blue).

Graphic: Sonja Lorenz


Sonja Lorenz and Postdoc Bodo Sander

Photo: Lena Ries

How ubiquitin exerts its diverse functions is intensely studied all over the world. Finding answers to this question is essential to exploit the ubiquitin system efficiently for therapeutic purposes. Researchers from Würzburg have taken a key step towards this goal. Their results reveal new ways of regulating a ubiquitin ligase.

Enzymes that determine a protein’s fate

“Ubiquitin ligases are enzymes that decorate cellular target proteins with ubiquitin and thus determine the fate of these target proteins,“ says Dr. Sonja Lorenz, senior author on the study. Ubiquitin can act as a “molecular postal code“ that can guide target proteins to specific locations in the cell, lead them to serve distinct functions, carry molecular signals, integrate into large complexes, or even be destroyed.

Sonja Lorenz heads a research group at the Rudolf Virchow Center for Experimental Biomedicine at the University of Würzburg. Her team and colleagues study a particular ubiquitin ligase, HUWE1, that has been ascribed key roles in tumor formation and is considered a promising, yet unexploited cancer-therapeutic target. Their new results on the molecular mechanism of HUWE1 are reported in the journal eLife.

Divide and rule: breaking down a protein giant

With almost 4.400 amino acids HUWE1 is an extremely large protein. Its three-dimensional structure, for the most part, is unknown. “The enormous size of HUWE1 and its flexibility present a considerable challenge for structural biologists,“ says Sonja Lorenz. To get a handle on the protein giant, her research team followed the ancient Roman principle “divide et impera – divide and rule” and has initially determined the atomic structure of a portion of HUWE1 using X-ray crystallography.
This structure reveals a new and intriguing feature of HUWE1: Two HUWE1 molecules can pair up to form a complex known as a “dimer”, thereby shutting down their enzymatic activities.

Imbalances with consequences

How does the cell prevent HUWE1 from forming dimers when the enzyme needs to be active? The Würzburg researchers also provide an answer to this question: HUWE1 exists in a fine-tuned balance of inactive dimers and single, active molecules. “Various cellular factors can regulate this balance,” says Sonja Lorenz.

The tumor suppressor protein p14ARF is one such factor. It inhibits HUWE1, but is frequently lost in cancer cells. The new study provides the first mechanistic explanation of how p14ARF inhibits HUWE1. “The effects of p14ARF on the structure and activity of HUWE1 are extremely exciting,” says Sonja Lorenz. “They open up a range of possibilities to manipulate HUWE1 activity that we are following up on.”

Personal details: Sonja Lorenz

Dr. Sonja Lorenz holds an Emmy Noether grant from the German Research Foundation with which she established her lab at the Rudolf Virchow Center of the University of Würzburg in April 2014. She is the deputy speaker of the new Research Training Group 2243, “Understanding Ubiquitylation: From Molecular Mechanisms to Disease“, that will start in April 2017. Her studies on the interplay of HUWE1 and p14ARF are supported by the Wilhelm Sander-Foundation for medical research.

The human ubiquitin ligase HUWE1 is regulated by a conformational switch. Bodo Sander, Wenshan Xu, Martin Eilers, Nikita Popov, Sonja Lorenz. DOI: 10.7554/eLife.21036

Contact details:

Dr. Sonja Lorenz, Rudolf Virchow Center for Experimental Biomedicine, phone: (0931) 31-80526, e-mail: sonja.lorenz@virchow.uni-wuerzburg.de

Gunnar Bartsch | Julius-Maximilians-Universität Würzburg
Further information:
http://www.uni-wuerzburg.de

More articles from Life Sciences:

nachricht One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie

nachricht The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Magnetic nano-imaging on a table top

20.04.2018 | Physics and Astronomy

Start of work for the world's largest electric truck

20.04.2018 | Interdisciplinary Research

Atoms may hum a tune from grand cosmic symphony

20.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>