This account traces the path to an unexpected and intriguing discovery of a novel zinc-containing minidomain, found in multiple copies in numerous proteins. The official version of events has focused on the work of Aaron Klug and his colleagues. Ignoring earlier discoveries and predictions made by many others. Important contributions have been left out of the story. Key facts gradually emerged over a period of two and a half decades. It all began in 1979 when an abundant protein p45 was found in the ovaries of some frogs and fish by Brigitte Picard. This p45 protein was stored in a small nonribosomal particle together with 5S rRNA.
Results soon followed from several different laboratories. Each research group working independently and probably unaware of the others’ interests. In 1980 Hugh Pelham showed that the p45 protein was identical to the transcription factor IIIA. A nucleic acid-binding protein somehow specific to both the DNA double helix and folded RNA. Then in 1983 zinc ions were found in TFIIIA by Jay Hanas and shown to be essential for the biological activity.
During 1984 the amino acid sequence of TFIIIA was determined by Donald Brown and also by Robert Roeder. The author and Patrick Argos identified multiple cysteine and histidine (C2H2) motifs in the sequence. Each motif containing a short DNA-binding alpha helix. In 1985 Aaron Klug and Andrew McLachlan independently observed the same amino acid-motif. These motifs were predicted to be small folded units containing zinc and were named zinc fingers. Several other zinc finger proteins were soon found in fruit flies by Alain Vincent.
In 1986 J. Yun Tso showed that six of the zinc fingers matched exons in the TFIIIA gene. Supporting the idea of minidomains or small folded units. A model of a single zinc finger was first proposed by Jeremy Berg in 1988. The predicted polypeptide fold was proved 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 nucleotide bases in the major groove of DNA. Confirming earlier predictions and models. In 1998 the author and Robert Nolte revealed more ways of binding to DNA. Finally in 2003 Duo Lu showed how three of TFIIIA zinc fingers interact with 5S rRNA.
The discovery of zinc fingers was not a result of model-building like that of James Watson and of 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. Other motifs with cysteines and histidines, which also bind zinc ions, 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]