length, contain a single transmembrane domain, and 
contain a protein kinase-like domain just within the 
transmembrane region. A deletion mutant contain- 
ing the cyclase catalytic domain and only a small 
part of the protein kinase domain contained guany- 
lyl cyclase activity. However, when analyzed on gel 
permeation columns, activity was only observed at 
the position of the homodimer. The chaotropic salt 
sodium trichloroacetate dissociated the dimer into a 
monomer and also destroyed activity. The full- 
length receptor migrated principally as a monomer 
on SDS-PAGE, but the prior incubation of mem- 
branes with ANP or with ANP and ATP resulted in the 
conversion of a small fraction of the monomer to a 
disulfide-linked dimer. Subsequent crosslinking ex- 
periments showed that GC-A exists as a dimer or 
higher-ordered oligomer in the absence of ANP. 
Therefore ANP does not induce receptor oligomeri- 
zation as seen with the growth factor receptors but 
likely causes conformational changes in an already 
existent dimer or tetramer. 
Dr. Garters is also Professor of Pharmacology 
at the University of Texas Southwestern Medical 
Center at Dallas. 
Books and Chapters of Books 
Garbers, D.L. 1991. Diversity of the guanylyl cy- 
clase family. In Peptide Regulation of Cardiovas- 
cular Function (Imura, H., Matsuo, H., and Ma- 
saki, T., Eds.). Tokyo: Academic, pp 79-89. 
Articles 
Garbers, D.L. 1991. Guanylyl cyclase-linked re- 
ceptors. Pharmacol Ther 50:537-545. 
Garbers, D.L. 1991. The guanylyl cyclase-receptor 
family. Can f Physiol Pharmacol 69:1618- 
1621. 
Potter, L.R., and Garbers, D.L. 1992. Dephosphor- 
ylation of the guanylyl cyclase-A receptor causes 
desensitization./iJ/o/ Chem 267:14531-14534. 
Schulz, S., Chrisman, T.D., and Garbers, D.L. 
1992. Cloning and expression of guanylin. Its ex- 
istence in various mammalian tissues. / Biol 
Chem 267:16019-16021. 
Wong, S.-K.F., and Garbers, D.L. 1992. Receptor 
guanylyl cyclases. / Clin Invest 90:299-305. 
Yuen, P.S.T., and Garbers, D.L. 1992. Guanylyl 
cyclase-linked receptors. Annu Rev Neurosci 
15:193-225. 
MOLECULAR ANALYSIS OF PROTEINS INVOLVED IN HUMAN DISEASE 
Mary-Jane H. Gething, Ph.D., Investigator 
Investigations in this laboratory of experimental 
models of human disease grow out of several years 
of basic research on the biochemical and structural 
properties of cellular and viral proteins. Studies 
supported by HHMI involve three systems: 1) hu- 
man tissue-type plasminogen activator (t-PA), a ser- 
ine protease involved in fibrinolysis, tissue remodel- 
ing, and metastasis; 2) the hemagglutinin (HA) of 
influenza virus, which is being used to develop mod- 
els of autoimmune disease in transgenic mice; and 
3) the tumor-suppressor protein p53 and its interac- 
tion with cytosolic stress-70 proteins. In addition, 
basic studies on the cellular role and regulation of 
protein chaperones are supported by the National 
Institutes of Health. 
Role of Tissue-Type Plasminogen Activator 
in Thrombolysis and Metastasis 
Many normal and abnormal biological processes 
that require extracellular proteolysis, including 
thrombolysis, tissue remodeling, and metastasis, are 
mediated by plasminogen activators that cleave 
plasminogen to the active protease plasmin. The 
t-PA is the principal thrombolytic agent in the circu- 
lation; elevated expression of t-PA is thought to 
be linked to increases in metastatic potential of 
some types of tumor cells, including malignant 
melanomas. 
The t-PA protein is composed of a number of inde- 
pendent structural domains that are encoded by indi- 
vidual exons in the t-PA gene. The finger and epider- 
mal growth factor (EGF)-like domains are involved 
in the initial, high-affinity binding of t-PA to fibrin, 
whereas stimulation of t-PA activity requires second- 
ary, lower affinity interactions of fibrin with either 
of the two kringle domains of the molecule. The 
binding of t-PA to specific clearance receptors on 
hepatic cells also involves sequences within the 
finger and/or EGF-like domains. Finally, the spe- 
cific inhibitor plasminogen activator inhibitor ! 
(PAI-1) interacts with the active site in the car- 
boxyl-terminal catalytic domain. 
CELL BIOLOGY AND REGULATION 59 
