Our group is mainly concerned with the structure and evolution of proteins. In this regard, we have two quite distinct projects under way. One is very general and has to do with reconstructing the evolutionary histories of a wide variety of proteins. This is a computer-based study that draws upon published sequence data for its raw material. We employ a number of sequence searching and alignment programs, many of which we have written ourselves. Among the questions we are trying to answer are: When did prokaryotic organisms diverge from eukaryotes? How many rudimentary families of proteins are there? How are "new proteins" invented? All of these questions can be answered, given enough sequences to compare
Our second major research interest is laboratory-based and deals with the invention and evolution of vertebrate blood plasma proteins, and expecially the clotting proteins. In the past, we have cloned and sequenced a number of these proteins from the most primitive of vertebrates, the lamprey. Comparison with the corresponding mammalian proteins has afforded us some important clues as to how these proteins function. We also succeeded in identifying equivalent gene products in even more distantly related creatures, including protochordates and invertebrates. Of all of these, we have focused most on the fibrinogen molecule. Our goal here is to understand how fibrin formation (clotting) occurs and was invented. In this regard, after many years of trying we managed to crystallize a native fibrinogen molecule (chicken fibrinogen = 320 KDa) and solved its X-ray structure. We have also solved the structure of various fibrinogen fragments with bound ligands involved in fibrin formation, and also factor XIII-generated crosslinked versions.
The crystallography project should shed light not only on how clotting works but also on where some of the components came from. Fibrinogen is a multidomained mosaic protein, a key part of which is found in numerous other animal proteins, including various cytotactins (e.g., tenascin and T-cell factors).
Crystal structure of fragment D from human fibrinogen
Yang, Z., Mochalkin, I., and Doolittle, R.F. (2000). A model of fibrin formation based on crystal structures of fibrinogen and fibrin fragments complexed with synthetic peptides. Proc. Natl. Acad. Sci., USA 97:14156-14161.
Yang, Z., Kollman, J., Pandi, L., Doolittle, R.F. (2001). Crystal structure of native chicken fibrinogen at 2.7A resolution. Biochemistry 40:12515-12523.
Doolittle, R.F. and York, A. (2002). Bacterial Actins? An Evolutionary Perspective. BioEssays 24:293-296.
Doolittle, R.F. (2002). Microbial Genomes Multiply. Nature 416:697-700.
Russell Doolittle received his Ph.D. from Harvard University. He was named a Guggenheim Fellow and was elected to the National Academy of Sciences and the American Academy of Arts and Sciences. Professor Doolittle is a co-recipient of the Paul Ehrlich Prize.