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
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
Dr. Sonja Lorenz, Rudolf Virchow Center for Experimental Biomedicine, phone: (0931) 31-80526, e-mail: firstname.lastname@example.org
Gunnar Bartsch | Julius-Maximilians-Universität Würzburg
More genes are active in high-performance maize
19.01.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn
How plants see light
19.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.
We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...
What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...
For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.
Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...
At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.
No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...
Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.
Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...
08.01.2018 | Event News
11.12.2017 | Event News
08.12.2017 | Event News
19.01.2018 | Materials Sciences
19.01.2018 | Health and Medicine
19.01.2018 | Physics and Astronomy