PRC2 (Polycomb Repressive Complex 2) is a protein that is important in embryo development, and also plays a key role in the progression of many cancers. Now an international research team has for the first time created a 3D model of the protein’s molecular architecture, which they hope will greatly increase understanding of birth defects and cancer linked to PRC2, and help the development of new and improved treatments.
Their findings are due to be published in a new journal called eLife, expected be launched this winter.
The team is led by biophysicist Eva Nogales, an electron microscopy expert with the US Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) in Berkeley, California, and one of two corresponding authors on the journal paper.
“Our model should also be an invaluable tool for the design of new experiments aimed at asking detailed questions about the mechanisms that enable PRC2 to function and how those mechanisms might be exploited,” says Nogales in a recent press statement.
The key role that PRC2 plays in embryo development is already well-known. The protein is important not just in human development but also that of many other organisms.
For instance, mouse studies have shown deletion of any of its components either leads to death of the embryo or severe defects.
Scientists have also shown than PRC2 helps control differentiation of embryonic stem cells into other types of cell: the protein silences key genetic messages in the cell nucleus to effect this, as Nogales explains:
“PRC2 controls stem cell differentiation by regulating the expression of specific genes through the binding and methylation of histones, the proteins in chromatin that help bundle DNA into nucleosomes.”
Such reasons are why the protein is what Nogales describes as one of the “top targets” for drug developers.
But, although so much is known about the protein’s biochemistry and molecular behavior, scientists don’t have much information about its architecture, and how its various structural parts interact to orchestrate histone binding and methylation: key processes for using DNA.
Nogales and colleagues produced their 3D model by painstakingly piecing together a jigsaw of data from many different sources, such as protein biochemistry, 3D electron microscopy, mass spectrometery, chemical cross-linking, and crystal structure docking.
The scale of the 3D model is measured in nanometers (billionths of a meter). The model shows PRC2 with all its subcomponents and functional areas making a complex with AEBP2, a co-factor protein that serves to stabilize PRC2.
The model shows the PRC2-AEBP2 complex comprises four large lobes, joined by two narrow arms, and clearly identifies where PRC2 and AEBP2 interact.
The researchers say their model clearly shows in unprecedented detail how AEBP2 helps stabilize PRC2, and how it helps orchestrate the activity of different subcomponents of PRC2.
Not only does it put previous biochemical data into perspective, the model should also serve as a tool for testing ideas about how PRC2 interacts with chromatin.
The 3D model should inspire further studies into how PRC2 works, say the researchers.
For instance, using the model, Nogales and colleagues have already pinpointed the subcomponents involved in histone binding and methylation: key processes for reading the DNA blueprint, and silencing genes during cell growth.
“PRC2 is recruited at specific sites along the DNA that need to be silenced, aided by regulators such as AEBP2,” explains Nogales.
Knowledge about the precise locations where this happens during gene silencing, “can be used to guide specific deletion or cross-linking mutants for future drug design efforts,” she adds.
Funds from the National Institute of General Medical Sciences, the Howard Hughes Medical Institute and from the European Union Seventh Framework Program PROSPECTS helped pay for the research.
Written by Catharine Paddock PhD