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The solenoid model


The importance of histones to chromatin structure
Aaron Klug Scientist
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He started by trying to make histone preparations, again of H3 and H4 and so on and trying to make them on a small scale and trying to aggregate them with small pieces of DNA, which we've got good fibres. But it was... it seemed to be clear that the way the histones were prepared we didn't know if they were native... in a native form or not. So I said to Roger [Kornberg], 'Can you try to look into', because he was a biochemist and he's trained by his father who as I said, was the best biochemist in the world. And Roger was very, very adept at biochemistry, making things. So he began to try to purify the individual histones, that is not just the H3 and H4 together, and the H2 and H2B together. In fact, they do go together as I'll say in a moment. And he... but in the meantime he took lots of X-ray pictures of different fractions interacting with DNA calf thymus. And we could gather all sorts of pics; we could see that on the whole there was some kind of interaction on a 100 angstrom scale that stood up in the X-ray pictures. Now, Wilkins and Luzzati interpreted the 100 angstroms as the pitch of the... as the... somehow the perodicity of a helix because they couldn't think of anything else by helices. And the idea was that the histones, like protamines folded around the DNA, clustered around and made some kind of knobbly structure. So the... but now, so Roger said... I said, we weren't sure about the condition for these histones and we tried different extracting conditions, different salts and all that and also tried to renature them. In the end, he read a paper by a group in South Africa, Van Holt and Van der Westhuizen who were working on sea urchin histones and he noticed that in the paper, they went through a step where the H3 and H4 were together. And the H2A and H2B were together, which were the... but in... in a reasonable form. And he thought that these might be denatured, un-denatured, so he followed it up and he adapted the prep and he made preparation and he made lots of material. And then he began to add them to DNA, both separately and... And together, again using X-ray diffraction because our guide was this 100 angstrom spacing and trying to recover it. It wasn't the best idea but that was all we had at the time, there's no enzymatic activity, the only thing you had was a structural indication. And we knew that if you took X-ray photographs of nuclei as a whole, and people had tried, you tend to get 100 angstrom lines, and also later on you could see 27 angstrom and 55 angstrom lines, that was done later. So he then thought that these might be and since the conditions under which they produce they went... they went on, then... sorry, I've forgotten, Van Holt and Van der Westhuizen went on to separate the histones. And Roger thought that maybe these go together naturally, which had been obvious indications of that. So he began to wonder what these aggregates were and he purified them, he also found that you could under the appropriate salt conditions you could add the H3 and H4 to H2A and H2B and form a really rather tight oligomer. And then he enlisted Jean Thomas, who was working in the biochemistry department, she was an expert protein chemist, which he wasn't. So she... they began to do cross-linking studies and he showed, between the two of them, they showed that H2A, H2B was a dymer, hetrodymer and H3, H4 was a tetramer, which was... so that was the... Now, these were and these looked like naturally existing aggregates. Now, you see, if this is the case, these are quite large and he also showed with Jean that you could put them together to make a histone octamer that is 1 H3 H4 tetramer and 2 H2A H2B dymers making an octamer. And this octamer seemed to be formed under a... and you could associate with DNA, you certainly recreated this 100 angstrom pattern and some other lines. So this was the psychological breakthrough because people had thought that the... that the histones coated the DNA. If they are forming octamers they couldn't possibly do that, they're much too large.

Born in Lithuania, Aaron Klug (1926-2018) was a British chemist and biophysicist. He was awarded the Nobel Prize in Chemistry in 1982 for developments in electron microscopy and his work on complexes of nucleic acids and proteins. He studied crystallography at the University of Cape Town before moving to England, completing his doctorate in 1953 at Trinity College, Cambridge. In 1981, he was awarded the Louisa Gross Horwitz Prize from Columbia University. His long and influential career led to a knighthood in 1988. He was also elected President of the Royal Society, and served there from 1995-2000.

Listeners: John Finch Ken Holmes

John Finch is a retired member of staff of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK. He began research as a PhD student of Rosalind Franklin's at Birkbeck College, London in 1955 studying the structure of small viruses by x-ray diffraction. He came to Cambridge as part of Aaron Klug's team in 1962 and has continued with the structural study of viruses and other nucleoproteins such as chromatin, using both x-rays and electron microscopy.

Kenneth Holmes was born in London in 1934 and attended schools in Chiswick. He obtained his BA at St Johns College, Cambridge. He obtained his PhD at Birkbeck College, London working on the structure of tobacco mosaic virus with Rosalind Franklin and Aaron Klug. After a post-doc at Childrens' Hospital, Boston, where he started to work on muscle structure, he joined to the newly opened Laboratory of Molecular Biology in Cambridge where he stayed for six years. He worked with Aaron Klug on virus structure and with Hugh Huxley on muscle. He then moved to Heidelberg to open the Department of Biophysics at the Max Planck Institute for Medical Research where he remained as director until his retirement. During this time he completed the structure of tobacco mosaic virus and solved the structures of a number of protein molecules including the structure of the muscle protein actin and the actin filament. Recently he has worked on the molecular mechanism of muscle contraction. He also initiated the use of synchrotron radiation as a source for X-ray diffraction and founded the EMBL outstation at DESY Hamburg. He was elected to the Royal Society in 1981 and is a member of a number of scientific academies.

Tags: Vittorio Luzzati, Maurice Wilkins, Roger Kornberg, Jean Thomas

Duration: 4 minutes, 59 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008