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J. Biol. Chem., Vol. 281, Issue 48, 39, December 1, 2006

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kresge, N. Articles by Hill, R. L. Search for Related Content PubMed Articles by Kresge, N. Articles by Hill, R. L. Related Collections Classic Articles Legaz et al. 248 (11): 3946 Lindquist et al. 253 (6): 1902 Social Bookmarking                      What's this?

Classics

The Waterfall Sequence for Blood Clotting: the Work of Earl W. Davie

Activation of Bovine Factor IX (Christmas Factor) by Factor XIa (Activated Plasma Thromboplastin Antecedent) and a Protease from Russell's Viper Venom (Lindquist, P. A., Fujikawa, K., and Davie, E. W. (1978) J. Biol. Chem. 253, 1902–1909)

Isolation and Characterization of Human Factor VIII (Antihemophilic Factor) (Legaz, M. E., Schmer, G., Counts, R. B., and Davie, E. W. (1973) J. Biol. Chem. 248, 3946–3955)

Earl Warren Davie was born in 1927 in Tacoma, Washington. He attended the University of Washington where he took a course in biochemistry taught by Donald Hanahan. Davie got his first taste of laboratory research when Hanahan invited him to work in his laboratory on a senior project. He enjoyed it immensely, and when he received his B.S. in 1950 Davie decided to remain at the University of Washington to do graduate studies. He chose to work with Hans Neurath to learn about protein structure and function. For his thesis research, Neurath suggested that Davie compare trypsinogen and trypsin to gain some insight into the mechanism of zymogen activation. As discussed in a previous Journal of Biological Chemistry (JBC) Classics article (1), this resulted in Davie and Neurath's isolation of an acidic peptide that was generated by limited proteolysis during the activation of trypsinogen. The appearance of this peptide correlated exactly with the formation of the enzymatic activity of trypsin. Little did Davie and Neurath realize that "limited proteolysis" would be a common mechanism seen over and over again in biological systems, including the blood coagulation to which Davie would eventually devote much of his research.

When Davie received his Ph.D. in 1954, Neurath recommended he do postdoctoral studies with JBC Classics (2) author Fritz Lipmann. Lipmann suggested that Davie try to isolate one of the amino acid carboxyl-activating enzymes that were thought to be involved in protein biosynthesis. In collaboration with Victor Koningsberger, Davie isolated and characterized a tryptophanyl carboxyl-activating enzyme that catalyzed the exchange of pyrophosphate into ATP in the presence of tryptophan and the formation of tryptophan hydroxymate when hydroxylamine was added to the reaction mixture (3).

After 2 years in Lipmann's laboratory, Davie accepted a faculty position in the Department of Biochemistry at Western Reserve University in Cleveland, Ohio. Davie's initial studies in Cleveland dealt with the isolation and identification of aminoacyl adenylates that had been proposed as intermediates in the carboxyl activation of amino acids. This led to his isolation and characterization of adenylyl tryptophan and adenylyl serine.

In 1957, Davie met Oscar Ratnoff, a distinguished Professor of Medicine and expert in blood coagulation at Western Reserve University. The meeting turned Davie's career in an entirely new direction as he began to collaborate with Ratnoff. Davie's first project with Ratnoff involved the isolation of a plasma protein that was missing from a patient named John Hageman whose blood didn't clot when added to a glass test tube. Using column chromatography, Davie was able to isolate the Hageman factor (4), which is now known as factor XII. A number of clinicians had identified several additional patients with different coagulation disorders due to missing plasma factors. It was clear to Davie that an understanding of how these proteins interacted to generate fibrin would require substantial protein purification. Accordingly, he and Ratnoff continued the purification of Hageman factor as well as PTA (plasma thromboplastin antecedent or factor XI) and Christmas factor (factor IX).

View larger version (152K): [in this window] [in a new window]   Earl W. Davie

Davie eventually showed that activated Hageman factor activated PTA which, in turn, activated Christmas factor. This demonstrated the concept that clotting factors were present in blood in an inactive or precursor form and were converted to active enzymes in a step-by-step manner most likely via limited proteolysis. This led to the coagulation scheme, shown in the figure seen here (5), that Davie and Ratnoff called a "waterfall sequence for intrinsic blood clotting." The waterfall sequence is sometimes referred to as the "waterfall cascade," and it results in the production of large amounts of thrombin and subsequently fibrin after the activation of very little of the factor that starts the cascade.

In the following years, Davie and his colleagues isolated and purified nearly all the plasma proteins in the cascade and determined the way they were activated. The second JBC Classic reprinted here compares the activation of Christmas factor by activated PTA and a protease from Russell's viper venom. Davie found that the activation of Christmas factor by the protease from Russell's viper venom was due to the cleavage of a single internal Arg–Val peptide bond in Christmas factor. PTA, on the other hand, activated Christmas factor in a two-step reaction in which an internal Arg–Ala bond is first cleaved and then an Arg–Val bond is cleaved. However, Davie determined that the critical step in the activation of Christmas factor by both pathways was the cleavage of the same Arg–Val peptide bond and the formation of a new NH₂-terminal sequence of Val-Val-Gly-Gly- in the heavy chain of the enzyme, which contains the active site serine residue.

Davie remains at the University of Washington where he still studies proteins involved in blood coagulation and fibrinolysis. Over the years he has modified the waterfall sequence, adding the extrinsic pathway (now called the tissue factor pathway) and linking it to the intrinsic pathway (now known as the contact activation pathway) at the level of the Stuart factor (factor X). Additional information about his research on blood coagulation can be found in Davie's JBC Reflections (6).

In recognition of his contributions to science, Davie has received many awards and honors. Among these are the International Prize from the French Association for Hemophilia (1983), the Waterford Bio-Medical Research Prize from the Scripps Clinic and Research Foundation (1985), the Robert P. Grant Medal from the International Society on Thrombosis and Hemostasis (1989), the Stratton Medal from the American Society for Hematology (1993), the Distinguished Achievement Award from the American Heart Association (1995), and the Bristol-Myers Squibb Award (1999). Davie served as Secretary for the American Society of Biological Chemists from 1975 to 1978 and was on the Board of Trustees of the Washington State Heart Association from 1974 to 1976. He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the Royal Danish Academy of Science and Letters. Davie has also served on the editorial board for the Journal of Biological Chemistry and is currently an Associate Editor of Biochemistry.¹

View larger version (20K): [in this window] [in a new window]   "Waterfall sequence for intrinsic blood clotting" from Ref. 5.

¹ Biographical information on Earl W. Davie was taken from Ref. 6.

REFERENCES

1. JBC Classics: Schwert, G. W., Neurath, H., Kaufman, S., and Snoke, J. E. (1948) J. Biol. Chem. 172, 221–239; Davie, E. W., and Neurath, H. (1955) J. Biol. Chem. 212, 515–530 (http://www.jbc.org/cgi/content/full/280/2/e1)
2. JBC Classics: Lipmann, F. (1945) J. Biol. Chem. 160, 173–190 (http://www.jbc.org/cgi/content/full/280/21/e18)
3. Davie, E. W., Koningsberger, V. V., and Lipmann, F. (1956) Arch. Biochem. Biophys. 65, 21–38[CrossRef][Medline] [Order article via Infotrieve]
4. Ratnoff, O. D., and Davie, E. W. (1962) The purification of activated Hageman factor (activated factor XII). Biochemistry 1, 967–974[CrossRef][Medline] [Order article via Infotrieve]
5. Davie, E. W., and Ratnoff, O. D. (1964) Waterfall sequence for intrinsic blood clotting. Science 145, 1310–1312[Abstract/Free Full Text]
6. Davie, E. W. (2003) A brief historical review of the waterfall/cascade of blood coagulation. J. Biol. Chem. 278, 50819–50832[Free Full Text]

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kresge, N. Articles by Hill, R. L. Search for Related Content PubMed Articles by Kresge, N. Articles by Hill, R. L. Related Collections Classic Articles Legaz et al. 248 (11): 3946 Lindquist et al. 253 (6): 1902 Social Bookmarking                      What's this?