< Wichtiger Schritt bei der Genexpression entschlüsselt
20.05.2016

Important step in gene expression revealed

Max-Planck researchers from Tübingen shed light on how the cell regulates the destruction of its internal messages


Tübingen, 19th of May 2016. Gene expression is a fundamental process in all living cells. There is an intermediary in this process – a molecule called messenger RNA. For the cell to function properly, this intermediary must not only be efficiently built but also be degraded. After almost two decades of research on one step of the degradation process called decapping, researchers of the Max Planck Institute for Developmental Biology in Tübingen, Germany, have now revealed how different molecules act together to enable decapping at the molecular level. Understanding this process helps to shed light on how genes are expressed and also onto the role of decapping in some types of cancer. The findings have been published in the journal Nature Structural & Molecular Biology.

During gene expression, the information content of the genes, stored in the DNA, is translated into proteins that then carry out biological mechanisms. Messenger RNA, or mRNA for short, acts as a carbon copy of the DNA and mediates this information transfer. In order to ensure the correct function of all cellular processes, mRNA must not only very rapidly be made but also be destroyed just as efficiently. If a certain mRNA persists for too long in the cell, it could lead to the dysregulation of biological mechanisms and eventually to disease. Much of the recent research on the molecular biology of cancer and disease has therefore been focused on discovering how the cell controls the levels of mRNA.

Unlike DNA, which exclusively exists in form of a double helix, mRNA molecules have very complex structures. In addition, extra molecular groups at either end of the molecule, called a ‘cap’ and a ‘tail’, serve to protect it from inadvertent and untimely destruction in the cell. To remove the protective groups, the cell has evolved highly efficient mechanisms, which then determine the speed of mRNA degradation. The tail is normally removed first, followed by the cap. Decapping is an irreversible step and any messenger RNA molecule lacking its cap is typically destroyed very rapidly.

Over the last 17 years researchers have studied decapping in order to understand how this process works at the molecular level and how this process impacts on the expression of genes. It was known that decapping is executed by an enzymatic protein, and that many other proteins regulate the efficiency of this enzyme. However, the understanding of how all of these proteins interact with each other and with the mRNA was missing. It was unclear why the main decapping enzyme, called Dcp2, needs to associate tightly with a smaller protein, called Dcp1, and how additional proteins, called “enhancers of decapping”, dramatically improve the activity of the decapping enzyme.

A research team from the Max Planck Institute of Developmental Biology in Tübingen, led by Prof. Dr. Elisa Izaurralde, has now demonstrated how all of these proteins act in concert at the molecular level. Using X-ray crystallography, a technique in which beams of highly focused X-rays are directed at crystallized proteins, the scientists have revealed the detailed atomic structure of the protein complex consisting of Dcp2, Dcp1, and the Edc1 enhancer protein. Whilst it had been known for some time that the structure of Dcp2 is quite flexible, the molecular role of this flexibility was not known. The scientists have now shown that the structural flexibility is critical for the regulation of Dcp2 activity. Dcp2 has to rotate by 120° – an enormous change for the structure of a protein. The rotation is stabilized only in the presence of the other two proteins, which therefore keep the Dcp2 enzyme in a highly activated state. In this state, mRNA molecules can form stronger interactions with Dcp2 and decapping can be executed efficiently.

The researchers studied the decapping complex from fission yeast, a model organism widely used in molecular biology. Very likely, however, the mechanism also occurs in humans because humans have very similar versions of all three proteins. This insight into a fundamental biological process will advance our understanding of the molecular mechanisms that regulate how genes are expressed.

Original Publication:Valkov, E. et al. :Structure of the Dcp2–Dcp1 mRNA-decapping complex in the activated conformation. Epub ahead of print. Nat Struct Mol Biol. 2016 May 16

doi:10.1038/nsmb.3232

 

Press contact:
Dr. Elisa Izaurralde
Phone:+49 7071 601-1350
E-Mail: elisa.izaurralde(at)tuebingen.mpg.de
Nadja Winter (PR Officer)Phone: +49 7071 601- 444
E-mail: presse-eb(at)tuebingen.mpg.de

 

 


Structure of the decapping complex, determined by X-ray crystallography. Stabilized by Dcp1 and Edc1 the catalytic subunit of Dcp2 undergoes a 120° rotation. The interaction of the three proteins causes the enzyme to adopt an active state that allows an efficient decapping of the mRNA. Eugene Valkov/ Max-Planck-Institute for Developmental Biology

Structure of the decapping complex, determined by X-ray crystallography. Stabilized by Dcp1 and Edc1 the catalytic subunit of Dcp2 undergoes a 120° rotation. The interaction of the three proteins causes the enzyme to adopt an active state that allows an efficient decapping of the mRNA. Eugene Valkov/ Max-Planck-Institute for Developmental Biology