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Solving the structure of a two-zinc finger construct


Class II zinc fingers and the effect zinc deficiency has on puberty
Aaron Klug Scientist
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We tried to crystallise the whole... there were various attempts... try to crystallise the whole of TF3A and also the TF3A bound to 5S RNA, when I talked about the... binding there's a 42 sediment... 42 S-particle, and a 7S-particle sets, sedimentation particle which are found in the ribosome, these are storage proteins, like the TF3A and so we tried to crystallise the 7S-particle, 42S was deemed to be too big and failed over many years, Louise Ferrel now joined the group and tried for a long time. In the meantime, Daniela Rhodes, Kyoshi and the guy in the lab had shown that... another transcription factor, in fact a SMI-five which is involved in yeast mating type, it switches on HO in the nuclease, they had found that... they'd shown that the DNA binding domain is enough to carry the... this very large protein to its target and so it was absolutely essential that this was... and other people began to show similar things. So these were a new class of DNA binding domains and that's what the zinc fingers are. And the numbers began to mount. Typically, proteins contain groups of fingers, maybe but usually not more than three or four in any one rung. But there is a protein called X-fin which has 37 zinc fingers. It's involved in Xenopus but it's divided up into groups... six or seven groups, I've forgotten now... which the discoverers called hands you see. Nobody knows what that does, so the numbers are growing.

But I want to return to other so-called zinc fingers and get them out of the way. Chambon in France and Ron Evans at the Salk were looking at a certain class of enzymes, transcription factors, involved in switching on nuclear transcription factors, these are nuclear genes and these are ligand driven, these are steroid and thyroid hormones, oestrogen receptor... and they found that the sequence contained... you had things in the sequence that looked like zinc fingers but you could... they had a fold of about the right shape, instead of two cysteines and two histidines, they had four cysteines so they... well... as I said Ron Evans didn't know enough chemistry but I think he read my paper and he thought it must be a zinc finger, you see... and Chambon tried to disprove that these things contained zinc by replacing the two cysteines by two histidines and of course the thing didn't fold up because it didn't have the right geometry, but there was a long story. Anyway, it turned out this is what they called 'class II zinc fingers'. And they are C4, four cysteines, but it turned out they're not like fingers at all because they do fold up, they have two helices in them, one helix is the recognition helix, that's like TF3A the other helix is the kind of strut but they operate as dimers and they bind two dimeric DNA sites. So they belong to quite a different category and they're not... although they use zinc and it turned out there are many other protein designs which involves zinc, use zinc to fold up. And the reason why they use zinc is very obvious.

In the nucleus, which is a strong reducing agent, you can't use SS bridges so zinc is used to help fold up proteins. Zinc in the next commonest metal to iron in the nucleus, and in fact I was able to suggest a diagnosis for a disease... I kept being invited to meetings you see, for zinc, and it turned out that a whole lot of people working in bio... as I've said, bioinorganic chemistry and at one meeting I heard about an Egyptian doctor called [Ananda S] Prasad who in the 1950s worked in Iraq and he found that certain young men suffered from not passing through puberty properly. Girls were inaccessible of course because of the culture and they... I heard this from somebody working at Georgia Tech, at a meeting and he said that when they brought up rats, female rats, on a zinc deficient diet they could never breed, never ovulate. And it was obvious what is was, they need zinc to fold up the nuclear receptor protein... if you haven't the zinc that can't have an oestrogen receptor and they don't pass through puberty... female rats don't develop, don't mature. That was happening in Iraq. Now the reason it's happening in Iraq is that the soil is very much, it's a clay soil, it's in the marsh areas of Iraq, the so-called marshes which Saddam tried to drain... or did drain, and so these clay... absorbed minerals and so they're zinc deficient and so they tested that and they are zinc deficient so it serves them right. Another nice little story how this throws light on a disease. So zinc is an essential part of the diet, as we all know that, but now we know why. And certainly, it is essential for passing through puberty.

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: Louise Ferrel, Daniela Rhodes, Pierre Chambon, Ron Evans, Ananda S Prasad

Duration: 6 minutes, 20 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008