The blueprint of the pores in the membrane surrounding the nucleus of biological cells has been unravelled by a team in which biochemists and computational biologists from the laboratories of Andrej Sali, Michael Rout and Brain Chait closely cooperated. This week, Nature devotes its front page and two articles to the research. Dr Liesbeth Veenhoff of the Enzymology Department of the University of Groningen is one of the main authors of both articles.
The reason why Nature is paying so much attention to this research is not only because the determination of the structure represents a breakthrough in biology. The method used is also new and extremely promising.
Pores in the membrane around the nucleus play a crucial role in the regulation of all kinds of processes within the cell. ‘The storage of DNA in a separate space has been one of the more important steps in evolution,’ says Veenhoff. ‘The fact that the membrane screens off the DNA and only allows substances to permeate via the pores on a selective basis enables the vast diversity of life forms that we currently see.’
The membrane, with its pores, regulates access to the DNA. In this way, the moment at which a particular gene can be read is neatly determined. The great significance of the structure is the fact that it is identical in all forms of life, ranging from yeast to humans. This is ideal for research because the blueprint of the pores, which has been determined with yeast cells, therefore applies to all life forms. In addition, it indicates that we are dealing with, in evolutionary terms, an old, well-preserved structure – something that nature is apparently rather frugal with.
The pores of the nuclear membrane comprise 456 proteins of thirty different types. The protein complex is so large that the pore can be seen with the help of an electron microscope. Cell biologists had previously observed that the proteins are arranged into eight clusters that jointly form a cylinder wall around the pore passageway. The new information concerns the precise coherence of the protein clusters.
The researchers first gathered structural information on the thirty different protein types: what was their exact composition and which form corresponds to this? Subsequently, the complexes were purified and a rough estimate was made of which proteins were close to one another. This information was translated into distance restraints. With the assistance of new computational methods, a search was performed into the structure that best fitted these data. The computer began by assuming random positions for each of the 456 proteins, and then shifted them step by step to the position that harmonized best with the restraints. This was a task that required enormous calculating capacity. In this case, an exceptionally powerful computer (200 CPU) was engaged in the calculation for no less than thirty days.
The researchers also discovered that the interior wall of the pore has long-threaded tentacles that ensure the transport of substances across the membrane. In this process, the tentacles work in unison with a so-called ‘chaperone’ protein. Having reached the interior, the proteins relate their message and certain parts of the DNA are read off. They may also provide a signal that the DNA should replicate itself, which is the first stage of cell division. Veenhoff: ‘Most functionality in biology comes from cooperation between proteins. Because we now know how the protein structure is composed, we can also comprehend the working mechanism.’
‘The structure we have discovered gives us insight into the transport mechanism,’ says Veenhoff. ‘But we also have a better understanding of how the pore originated in the evolutionary process. The structure displays a great deal of symmetry. The thirty proteins all have a ‘sister’ that occupies a similar position. From this, you can deduce that the pore complex originated as the result of several gene duplications from a much simpler primal version.’
Frank Alber, Svetlana Dokudovskaya, Liesbeth M. Veenhoff, et al.: The molecular architecture of the nuclear pore complex. Frank Alber, Svetlana Dokudovskaya, Liesbeth M. Veenhoff, et al.: Determining the architecture of macromolecular assemblies.
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