Nav: Home

Ubiquitous and influential

February 14, 2017

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. 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."
-end-
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

University of Würzburg

Related Protein Articles:

Hi-res view of protein complex shows how it breaks up protein tangles
A new, high-resolution view of the structure of Hsp104 (heat shock protein 104), a natural yeast protein nanomachine with six subunits, may show news ways to dismantle harmful protein clumps in disease.
Breaking the protein-DNA bond
A new Northwestern University study finds that unbound proteins in a cell break up protein-DNA bonds as they compete for the single-binding site.
FASEB Science Research Conference: Protein Kinases and Protein Phosphorylation
This conference focuses on the biology of protein kinases and phosphorylation signaling.
Largest resource of human protein-protein interactions can help interpret genomic data
An international research team has developed the largest database of protein-to-protein interaction networks, a resource that can illuminate how numerous disease-associated genes contribute to disease development and progression.
STAT2: Much more than an antiviral protein
A protein known for guarding against viral infections leads a double life, new research shows, and can interfere with cell growth and the defense against parasites.
More Protein News and Protein Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#534 Bacteria are Coming for Your OJ
What makes breakfast, breakfast? Well, according to every movie and TV show we've ever seen, a big glass of orange juice is basically required. But our morning grapefruit might be in danger. Why? Citrus greening, a bacteria carried by a bug, has infected 90% of the citrus groves in Florida. It's coming for your OJ. We'll talk with University of Maryland plant virologist Anne Simon about ways to stop the citrus killer, and with science writer and journalist Maryn McKenna about why throwing antibiotics at the problem is probably not the solution. Related links: A Review of the Citrus Greening...