| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 281, Issue 14, 11, April 7, 2006
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Side-chain Interactions Governing the Pairing of Half-cystine Residues in Ribonuclease
(Haber, E., and Anfinsen, C. B. (1962) J. Biol. Chem. 237, 1839–1844)
Christian Boehmer Anfinsen, Jr. (1916–1995) was born in Monessen, Pennsylvania, a small town just south of Pittsburgh. In 1933, he enrolled at Swarthmore College where he studied chemistry and played football while working as a waiter in the dining hall. He received his B.S. in 1937 and then pursued graduate study at the University of Pennsylvania, working toward an M.S. degree in organic chemistry and serving as an assistant instructor. He graduated in 1939 and received a fellowship from the American Scandinavian Foundation to spend a year at the Carlsberg Laboratory in Copenhagen developing new methods for analyzing the chemical structure of complex proteins, namely enzymes. When he returned to the United States in 1940, he entered Harvard University's Ph.D. program in biochemistry. In 1943 he received a Ph.D. in biochemistry for his dissertation, entitled "Quantitative Histochemical Studies of the Retina."
From 1944 to 1946 Anfinsen worked in the United States Office of Scientific Research and Development and studied the metabolism of blood in both healthy monkeys and monkeys infected with malarial parasites. He then resumed teaching at Harvard Medical School, where he eventually became an assistant professor of biochemistry. Over the next decade, his research shifted from examining the metabolic processes of tissues to focusing on biochemical processes at the molecular level. This shift in focus was part of a growing scientific trend, and many scientists were making the transition from cellular to molecular biochemistry at that time.
In 1950, Anfinsen was invited to become Chief of the Laboratory of Cellular Physiology at the National Heart Institute, part of the National Institutes of Health (NIH). Upon his arrival at the NIH, Anfinsen started investigating the structure of bovine pancreatic ribonuclease. This decision was partly practical: the Armour meat packing company of Chicago could provide Anfinsen's laboratory with a ready supply of raw material. Another research team headed by Stanford Moore and William Stein was working simultaneously on ribonuclease, and in 1960, Moore and Stein were able to determine the exact amino acid sequence of the enzyme. This was the subject of a previous Journal of Biological Chemistry (JBC) Classic (1). Anfinsen continued on with his ribonuclease studies as he was more concerned with how the enzyme folded into its active configuration.
He found that reduction of ribonuclease in an aqueous solution of concentrated guanidine HCl containing 
-mercaptoethanol led to complete loss of its enzymatic activity. On exposure to air after removal of the guanidine HCl the ribonuclease spontaneously reoxidized and regained its full enzymatic activity. Because ribonuclease contains 8 sulfhydryl groups, leading to 105 possible arrangements with 4 disulfide bonds, Anfinsen believed that certain interactions must guide the formation of the correct disulfide bonds. In other words, the information determining the tertiary structure of the protein resided in the chemistry of its amino acid sequence. In order to verify this, Anfinsen carried out oxidations of reduced ribonuclease in the presence of various reagents known to influence inter- and intramolecular bonding. This is the subject of the JBC Classic reprinted here.
|
Investigations on the reversible denaturation of several additional proteins served to verify Anfinsen's thermodynamic hypothesis. Also, further studies on the rate and extent of renaturation led to his discovery of a microsomal enzyme that catalyzes sulfhydryl-disulfide interchange. For his discovery that the amino acid sequence of a protein determines its native conformation and the conformation determines its biological activity, Anfinsen received half of the 1972 Nobel Prize for Chemistry. Moore and Stein were awarded the other half. These observations established the important principle of protein chemistry that a gene determines the amino acid sequence of a protein, the sequence determines the native conformation, and the conformation determines the biological activity.
Anfinsen's later work concerned a variety of topics, including staphylococcal nuclease, interferon, and the proteins of hyperthermophilic bacteria. Anfinsen remained at the NIH until 1962 when he returned to Harvard Medical School as a visiting professor and was promptly invited to become Chair of the Department of Biological Chemistry. The NIH, however, wooed Anfinsen back, and he was appointed Chief of the new Laboratory of Chemical Biology at the National Institute of Arthritis and Metabolic Diseases. He held this position until 1981, then spent a year at the Weizmann Institute of Science, and then in 1982 accepted an appointment as professor of biology at Johns Hopkins University.
In addition to the Nobel Prize, Anfinsen has received many other honors including the Rockefeller Public Service Award (1954), membership in the Vatican's Pontifical Academy of Science (1981), the Hebrew University of Jerusalem Medal (1985), and the National Library of Medicine Medal (1986). He has also received honorary degrees from seven universities, including Georgetown University and New York Medical College. Anfinsen was elected to the National Academy of Sciences in 1963 and the Royal Danish Academy in 1964. He was an editor of the journal Advances in Protein Chemistry and served on the editorial boards of both the Journal of Biological Chemistry and the Proceedings of the National Academy of Sciences. Anfinsen also wrote "The Molecular Basis of Evolution," which was published in 1959. He was active as a member of the Board of Governors of the Weizmann Institute of Science in Rehovot, Israel, and was elected President of the American Society of Biological Chemists in 1971.1
Anfinsen's coauthor on this JBC Classic also went on to make important contributions to science. Edgar Haber (1932–1997), who earned his A.B. (1952) and M.D. (1956) from Columbia University (1952), was a research associate at the Laboratory of Cellular Physiology when he published the paper with Anfinsen. He eventually became an eminent research cardiologist and immunologist who spent most of his career at Massachusetts General Hospital, where he was chief of the cardiology department for 24 years, and at Harvard Medical School, where he was Higgins Professor of Medicine. He was also president of the Squibb Institute for Medical Research from 1988 to 1990 and of the Bristol-Myers Squibb Pharmaceutical Research Institute from 1990 to 1991.
Haber's research focused mainly on the molecular biology and immunology of cardiovascular disease. He achieved worldwide recognition for inventing the immunoassay for digoxin, which resulted in improved understanding of the digitalis glycosides, and in a specific antidote for digitalis toxicity; for discovering an immunoassay for renin and elucidating of the role of the renin-angiotensin system in maintenance of blood pressure; and for being the first to use antibodies in cardiovascular radioimaging. In recognition of his work, Haber received the International Society of Hypertension's Volhard Prize (1980), the College of Physicians and Surgeons' Joseph Mather Smith Prize (1991), and the American College of Cardiology's Distinguished Scientist Award (1991) and was elected to the American Academy of Arts and Sciences.
FOOTNOTES
1 All biographical information on Christian Anfinsen was taken from Refs. 2 and 3. 
REFERENCES
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
