Structural Studies of Molecules Involved in the 
Immune Recognition of Infected Cells 
Pamela J. Bjorkman, Ph.D. — Assistant Investigator 
Dr. Bjorkman is also Assistant Professor in the Division of Biology at the California Institute of Technol- 
ogy and Adjunct Professor of Biochemistry at the University of Southern California School of Medicine, 
Los Angeles. She received a B.A. degree in chemistry from the University of Oregon and then a Ph.D. degree 
in biochemistry and molecular biology from Harvard University, where her thesis advisor was Don Wiley. 
She completed a crystal structure analysis of a human histocompatibility molecule for her thesis and then 
stayed on to finish the work. She continued her postdoctoral training at Stanford University in the labo- 
ratory of Mark Davis, before joining the staff at Caltech. 
THE technique of x-ray crystallography allows 
visualization of the three-dimensional struc- 
tures of proteins in atomic detail. In other words, 
we get a picture of the protein that shows the 
location of all the atoms and how they interact. 
The shape of a protein and the location of individ- 
ual atoms with respect to one another are impor- 
tant for determining how the protein functions. 
With such knowledge it is often possible to de- 
sign compounds that modify the protein for medi- 
cal intervention. 
The proteins that we are studying structurally 
are those that mediate the immune response 
against viruses and other pathogens. The immune 
system has evolved so that highly specific mol- 
ecules on the surfaces of lymphocytes can recog- 
nize a virally infected cell. In the infected cell, 
pieces of viral proteins are fragmented and bound 
to a cellular protein called a histocompatibility 
molecule. If the complex formed between the 
histocompatibility molecule and the viral frag- 
ment is recognized by a protein on the lympho- 
cyte, the infected cell is destroyed. The lympho- 
cytes that bear the recognizing proteins are T 
cells, and the proteins on their surface are T cell 
receptors. 
My previous work in the laboratory of Don Wi- 
ley (HHMI, Harvard University) used x-ray crystal- 
lography to determine the structure of a histo- 
compatibility molecule. We learned how and 
where viral molecules bind to histocompatibility 
protein and how T cell receptors might bind to 
this complex. My laboratory now seeks to deter- 
mine a three-dimensional structure for a T cell 
receptor, in order to understand the atomic de- 
tails of its interaction with the surface of an 
infected cell. (This work is being done in collabo- 
ration with Mark Davis, HHMI, Stanford Univer- 
sity.) We will also try to make crystals of a 
complex between a T cell receptor and histocom- 
patibility molecule to be used in a three-dimen- 
sional structure determination. An understanding 
of how T cell receptors interact with histocompat- 
ibility molecules complexed to viral fragments 
should increase our understanding of how the 
immune system distinguishes normal, healthy 
cells from virally infected cells that need to be 
destroyed. 
Our laboratory is also using protein expression 
systems in mammalian and bacterial cells to pro- 
duce the large quantities of proteins necessary for 
crystallization and structural studies. Using mo- 
lecular biological techniques, it is possible to 
transfect a protein-encoding gene into a cell in 
which it is not normally found, thus persuading 
the cell to manufacture that protein. Many pro- 
teins normally occur in small quantities; the use 
of such protein expression systems allows the 
isolation of much more of these proteins than 
would be otherwise possible. We have expressed 
fragments of histocompatibility molecules in bac- 
teria in preparation for making complexes be- 
tween these proteins and antigenic peptides. We 
are also working on protein expression in mam- 
malian cells. 
In collaboration with Kai Zinn at Caltech, we 
have expressed in a hamster fibroblast cell line 
large quantities of a cell surface protein found in 
the grasshopper and fruit fly nervous systems. We 
are interested in the structure of this molecule, 
because many molecules involved in cell surface 
recognition in the immune and nervous systems 
are related to each other. This protein has now 
been purified and crystallized. We are continuing 
to investigate ways to improve the quality of the 
crystals, as the current crystals do not diffract to 
sufficient resolution to allow a crystal structure 
determination. 
We have also used a similar protein expression 
system to make an Fc receptor, a protein that 
binds to the Fc portion of antibody molecules. 
(This work is in collaboration with Neil Simister, 
Brandeis University.) This particular Fc receptor 
is found in the intestine of newborn mammals 
and binds maternal immunoglobulin in milk, 
thus transferring partial immunity from mother to 
infant. The amino acid sequence and structural 
organization of this molecule show similarities to 
histocompatibility molecules. We have made a 
soluble (non-membrane-bound) version of this 
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