This account describes the path to an unexpected and intriguing discovery of a novel metal-containing minidomain, found in multiple copies in thousands of proteins. The official version of events has focused on the work of Aaron Klug and his colleagues. Ignoring earlier discoveries and predictions made by others. Their important contributions have been left out of the story. Key facts gradually emerged over a period of two and a half decades. It began in 1979 when an abundant protein p45 was found in the ovaries of some frogs and fish by Brigitte Picard. p45 was stored in a particle with 5S rRNA. Results soon followed from several different laboratories. Each working independently and probably unaware of the others interests. In 1980 Hugh Pelham showed that p45 was identical to the transcription factor TFIIIA. A dual nucleic acid-binding protein somehow specific to both the DNA double helix and folded RNA. Then in 1983 Jay Hanas found that zinc ions were present in TFIIIA and essential for its biological activity.
During 1984 the amino acid sequence of TFIIIA was determined by Donald Brown and Robert Roeder. The author and Patrick Argos identified multiple cysteine and histidine (C2H2) motifs in the sequence. Each motif containing a likely DNA-binding alpha helix. Followed later in 1985 by Aaron Klug and Andrew McLachlan, who independently observed the same amino acid-motif. These motifs were predicted to be small folded units and named zinc fingers.
In 1986 J. Yun Tso found that six of the zinc fingers matched exons in the TFIIIA gene. Supporting the idea of minidomains or small folded units. A molecular model of a single zinc finger was proposed by Jeremy Berg in 1988. This polypeptide fold was soon shown to be correct by Min Lee in 1989. Then In 1992 Nikola Pavletich succeeded in solving a zinc finger-DNA structure at atomic resolution. Short alpha helices in zinc fingers bind to the major groove of DNA. Confirming earlier predictions. Finally in 2003 Duo Lu showed how some of the TFIIIA zinc fingers interact with 5S rRNA.
The discovery of zinc fingers did not result from an epic model-building effort like that of James Watson and Francis Crick in 1953. Zinc fingers were found in the amino acid sequence of TFIIIA. Their existence in TFIIIA was deduced from the remarkable pattern of sequence repeats. Similar motifs containing combinations of cysteines and histidines, which also bind zinc ions, have been discovered in a variety of proteins that control gene expression.
“One finds that in the history of science almost every problem has been worked out by someone else”. Theodore von Kármán (1967) ii
Endnotes
i Gore, Al. (2007). An Inconvenient Truth. Penguin. New York, NY.
ii von Kármán T & Lee E. (1967). The Wind and Beyond: Theodore von Kármán, Pioneer inAviation and Pathfinder in Space. Little Brown & Co, Boston.