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
Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
19.07.2018 | Earth Sciences
19.07.2018 | Power and Electrical Engineering
19.07.2018 | Materials Sciences