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"Pac-Man" discovered in cell nucleus

Human genes are not always equally active, they are regulated by molecular switches among other mechanisms. In a current publication Dr. Alwin Köhler, together with an international team, is presenting how the protein complex SAGA activates one of these switches.

(Vienna, 18 May 2010) The 25,000 human genes are not equally active in the course of our lives, and activating molecular switches is one way their activity is regulated. In a current publication in the international top journal "Cell" Dr. Alwin Köhler from Max F. Perutz Laboratories of MedUni Vienna, together with an international team, is presenting how the protein complex SAGA activates one of these switches.

The DNA in a human cell comprises 3 billion base pairs and has a total length of approximately 1.8 metres. To ensure that the DNA has enough space in the cell nucleus, it is wound tightly around histone proteins, which resembles a pearl necklace under an electron microscope.

The DNA serves as the blueprint for the production of proteins. Depending on which proteins are to be produced, certain DNA sequences – the genes that are responsible in the specific case – are "read" (transcribed). For this the DNA has to be disengaged from the histone if necessary. Here the small protein ubiquitin helps, which must first be attached to the histones as a marker. When ubiquitin is later separated from the histone, a gene can be read. For this important step an enzyme is responsible – deubiquitinase Ubp8 – which was analysed in detail during Alwin Köhler's study. "In our study we have decoded the structure and function of Ubp8. It looks a bit like a small Pac-Man who bites the ubiquitin from the histones," he explains. "Now the second question was how this Pac-Man is controlled so that he bites at the right place and time."

By itself, the enzyme Ubp8 is inactive because the uncontrolled removal of ubiquitin, a universal signalling molecule, would easily lead to chaos in the cell. The interaction of three other proteins is required to activate Ubp8. Only when all three activators have linked to Ubp8 can the Pac-Man work and separate ubiquitin from histones. "The special feature of this mechanism is that Ubp8 is activated in several steps and that the three regulator proteins have specific tasks, namely to keep the Pac-Man together, identify the histone and open up the 'food centre'.

The test object used by the scientists was baker's yeast (Saccharomyces cerevisiae), which can be genetically manipulated relatively easily. As many proteins and processes in yeasts and people are very similar at the molecular biological level, these findings can be transferred to higher organisms and can help improve the understanding of different diseases.
The human equivalent of protease Ubp8 (USP22) is frequently overactive in tumour cells, for example, whereas malfunctions of one of the activators – known in humans as ataxin-7 – are involved in neurodegenerative diseases. Although it has been possible to identify the interaction of the activators and Ubp8, many questions are still open, says Köhler: "The three activators of Ubp8 seem to fulfil many other functions for gene regulation. Although we have put together part of the jigsaw, there is still a lot of work ahead of us before we can see the full picture!"

Original publication:
Alwin Köhler, Erik Zimmermann, Maren Schneider, Ed Hurt, Ning Zheng:
» “Structural Basis for Assembly and Activation of the Heterotetrameric SAGA Histone H2B Deubiquitinase Module”; Cell, April 2010

Short biography:
Dr. Alwin Köhler has been Junior Group Leader at Max F. Perutz Laboratories of MedUni Vienna since the beginning of this year and, with his group, is researching this complex mechanism of gene regulation and the organisation of the cell nucleus. Before this he was employed at the Biochemistry Centre of Heidelberg University, where he also worked on the study that has now been published together with partners from the USA (Ning Zheng, University of Seattle).