This account traces the path to the discovery of a novel zinc-containing mini domain, found in multiple copies in numerous proteins. The oft-stated official version of events has focused on the work of Aaron Klug and his colleagues. But this is a highly selective and curated history that ignores earlier discoveries and predictions. Key facts gradually emerged over a period of two and a half decades.
In 1979 an abundant protein named p45 was found in the ovaries of certain frogs and fish by Brigitte Picard. This p45 protein was stored with 5S rRNA in a non ribosomal particle. Results soon followed from several laboratories. Each research group working independently and probably unaware of the others’ interests. In 1980 Hugh Pelham showed that p45 was identical to the transcription factor TFIIIA. A protein binding specifically to the DNA double helix and also to folded RNA. Then in 1983 Jay Hanas showed 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 zinc ligands and a likely DNA-binding alpha helix. In TFIIIA zinc plays a structural role and not a catalytic one. Then early in 1985 Aaron Klug and Andrew McLachlan independently identified the same amino acid-motif. These motifs were predicted to be small folded units and were named zinc fingers. Several other zinc finger proteins were soon discovered in fruit flies by Alain Vincent.
In 1986 J. Yun Tso found that six of the zinc fingers matched exons in the TFIIIA gene. Supporting the idea of mini domains or small folded units. A molecular model of a single zinc finger was proposed by Jeremy Berg in 1988. This polypeptide fold was proved experimentally by NMR 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 the zinc fingers bind to the major groove of DNA. Confirming earlier predictions and models. In 1996 the author and Robert Nolte revealed more ways zinc fingers bind to DNA. Finally in 2003 Duo Lu showed how three 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 first identified in the amino acid sequence of TFIIIA. Their existence was deduced from the remarkable pattern of sequence repeats. Similar motifs with cysteines and histidines, which also bind zinc, occur 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 in Aviation and Pathfinder in Space. Little Brown & Co, Boston.
Reviews
Caught with One’s Zinc Fingers in the Genome Integrity Cookie Jar. Vilas CK, Emery LE, Denchi EL, Miller KM. (2018) Trends Genet. 34, 313-325. [PMC free article]
Zinc finger proteins: guardians of genome stability. Kamaliyan Z, Clarke TL. (2024) Front Cell Dev Biol. 12, 1448789. [PMC free article]