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COMPLEXES MAKETH COMPLEXES

CCT checkpoint function regulating early steps in TFIID assembl

CCT checkpoint function regulating early steps in TFIID assembly. TAF5 emerging from the ribosome is captured by CCT and handed over to preformed TAF6/TAF9 complex, nucleating holo-TFIID formation. Professor Imre Berger

Press release issued: 6 December 2018

Multiprotein complexes catalyse most if not all vital cellular processes. Many of these amazing molecular assemblies are built from dozens of protein subunits which come together to exert their function. An international team of scientists led by Marc Timmers in Freiburg, Germany and Imre Berger in Bristol, has now revealed mechanisms at work when our cells put together these intricate nanomachines.

The Berger lab at the School of Biochemistry, Bristol University, researches multiprotein complexes that regulate gene expression, the process how hereditary information within our DNA is realized. Intriguingly, subunits present in one transcription complex may occur at given times in several other complexes, raising the question how the cell manages this daunting complexity. “Structural biology, in particular the recent ‘cryo-EM revolution’, provides amazing images of many essential complexes in cells” explains Imre Berger. “Looking at those images it becomes evident that complexes will not just form randomly from their parts.”

“Cells are generally extremely efficient with managing their chores, and gene transcription in particular is a highly controlled process” adds Marc Timmers from the German Cancer Consortium, University Freiburg. “Dedicated mechanisms must therefore exist to regulate complex assembly, however, the underlying mechanisms are poorly understood”.

The Berger and Timmers teams joined forces to tackle this enigma. Using X-ray crystallography, they determined the atomic structure of a complex of three proteins (TAF5, TAF6 and TAF9) that represents a central scaffold within human transcription factor TFIID, vital to transcription of all genes. This enabled the design of mutations to probe interfaces between the three proteins in vivo by cell-based assays and proteomics. Intriguingly, the studies revealed an unexpected checkpoint function by a different multiprotein complex, CCT, in TFIID assembly. CCT seemingly holds on to TAF5 when it emerges from the ribosome until a pre-assembled TAF6/TAF9 complex arrives. A molecular hook is then formed by TAF9, inserting into CCT and liberating TAF5 to form TAF5/TAF6/TAF9, thus nucleating holo-TFIID formation.

“We were thrilled by this discovery which made us rethink complex assembly” conclude Simona Antonova and Matthias Haffke, first authors of the study. “Of course, this is just the beginning. We now need to figure out how further TFIID subunits are put on top and which other complexes are involved, and how, in turn, they are assembled. Exciting times are ahead of us.”

Further information

CCT/TFIID assembly paper in Nature Structural and Molecular Biology (https://www.nature.com/articles/s41594-018-0156-z)

Marc Timmers at Freiburg University (https://www.med.uni-freiburg.de/en/faculty/our-professors-1/timmers-en)

Imre Berger at University of Bristol (www.bris.ac.uk/biochemistry/people/imre-berger/index.html

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