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Researchers Unravel How TOPLESS Co-Repressor in Plants Interacts with Other Molecules to Turn Genes Off; Work Provides a General Model for Type of Gene Silencing

Scientists at Van Andel Research Institute (VARI), in Grand Rapids, Michigan, have revealed an important molecular mechanism in plants that has significant similarities to certain signaling mechanisms in humans, which are closely linked to early embryonic development and to diseases such as cancer. In plants, as in animals and humans, intricate molecular networks regulate key biological functions, such as development and stress responses. The system can be likened to a massive switchboard--when the wrong switches are flipped, genes can be inappropriately turned on or off, leading to the onset of diseases. Now, VARI scientists have unraveled how an important plant protein, known as TOPLESS, interacts with other molecules responsible for turning genes off. The findings in plants provide a general model across species for this type of gene silencing, which is linked to several vital biological functions in humans. The discovery was published in the July 3, 2015 issue of Science Advances. The article is titled "Structural Basis for Recognition of Diverse Transcriptional Repressors by the TOPLESS Family of Corepressors." This is really a fundamental discovery--our structure shows the co-repressor TOPLESS interacting with key repressor motifs, which constitutes a major component of gene silencing in plants," said Van Andel Research Institute's Karsten Melcher, Ph.D., one of the study's corresponding authors. "Understanding this interaction in plants gives us unique insight into similar pathways in humans that involve these proteins, which are notoriously tough to investigate." Using X-ray crystallography, the team determined the three-dimensional structure of TOPLESS, both on its own and when linked with other molecules responsible for turning genes off, thereby regulating gene expression. Although these interacting molecules were chosen from different signaling pathways in plants, they all linked up with TOPLESS in the same manner.

"This structure will allow us to take a more targeted approach to investigating TOPLESS's counterparts in humans and significantly expands our knowledge base," said VARI's H. Eric Xu, Ph.D., who is also a corresponding author on the paper. "We're extremely excited to continue this work to better understand these proteins and how they interact with other molecules in health and disease states."

The new paper is the third in a trio of publications that unveil key components of fundamental molecular processes. Although the new study provides further insight into human molecular pathways, the work also directly describes how components of the molecular switchboard in plants interact to regulate responses to a multitude of stressors, including temperature fluctuations.

The new findings follow an earlier Nature paper, which was included in the top ten list of scientific breakthroughs of 2009 by Science magazine, and an earlier Science paper, both of which describe how plants respond to drought and temperature stress. Taken together, the papers not only have implications for developing hardier plants, but also for determining molecular structures for components of entire pathways.

In addition to those previously mentioned, authors of the new Science Advances paper include Jiyuan Ke, Honglei Ma, and Xin Gu of VARI and VARI-Shanghai Institute of Materia Medica; Jiayang Li of the Chinese Academy of Sciences; Joseph S. Brunzelle of Northwestern University; and Adam Thelen, now at Michigan State University.

ADDITIONAL BACKGROUND INFORMATION ON TOPLESS AND GENE REGULATION

Gene expression is regulated by both activators and repressors. Although gene repression is thought to be equally as important as gene activation for this regulation, relatively little is known about the mechanisms of gene repressors and co-repressors.

TOPLESS functions as a co-repressor and interacts with repressors containing ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motifs. EAR motifs are the most common form of transcriptional repression motifs found in plants and are thought to facilitate stable epigenetic regulation of gene expression via recruitment of chromatin modifiers.

TOPLESS plays important roles in plant development; its name stems from the fact that mutations in TOPLESS can give rise to seedlings in which the shoot is transformed into a second root, hence "topless" seedlings.

In humans, similar proteins also are altered in many types of tumors, and control embryonic development and the development of neurons.

The image shows the tetrameric TOPLESS complex with the EAR motif peptides bound at its repressor-peptide binding grooves. The repressor peptides are shown as a ball presentation. Credit: Karsten Melcher, Ph.D., Van Andel Research Institute).

[Press release] [Science Advances article]