Understanding the mechanism of information 
transfer from one to three dimensions, as in the fold- 
ing of proteins, remains a major unsolved problem 
in molecular biology. The laboratory of Assistant In- 
vestigator Peter S. Kim, Ph.D. (Massachusetts Insti- 
tute of Technology) uses small proteins and protein 
fragments to investigate the pathway of protein fold- 
ing and the structures of folding intermediates. The 
interaction between macromolecules is central to 
much of molecular physiology. The group is particu- 
larly interested in the leucine zipper class of DNA- 
binding proteins, and they wish to understand the 
code for specificity and stability of leucine zipper 
interactions. Postulated rules involved in protein 
folding and macromolecular recognition are being 
tested by trying to design amino acid sequences that 
fold into specific conformations and/or that interact 
in a predetermined manner with other molecules. 
Studies in the laboratory of Investigator John A. 
Glomset, M.D. (University of Washington) have 
provided evidence regarding the influence of poly- 
unsaturated fatty acids on the structure of animal 
cell membranes, the characteristics of a key enzyme 
in a newly discovered pathway of membrane phos- 
pholipid biosynthesis, and the role of the low- 
density lipoprotein receptor in promoting the deliv- 
ery of arachidonic acid for eicosanoic production in 
human blood monocytes. Further experiments are 
under way in each of these areas, as well as studies 
designed to explore the association of proteins that 
contain covalently bound isoprenoid groups with 
cell membranes. 
The most significant achievement of the research 
of Investigator Kevin P. Campbell, Ph.D. (University 
of Iowa) and his colleagues during the past year has 
been the demonstration that dystroglycan (43/1 56- 
kDa dystrophin-associated glycoprotein) is a novel 
laminin-binding glycoprotein and the suggestion 
that the function of the dystrophin-glycoprotein 
complex is to provide a linkage between the subsar- 
colemma cytoskeleton and the extracellular matrix. 
The findings of this group strongly support the hy- 
pothesis that in Duchenne muscular dystrophy a dra- 
matic reduction in dystroglycan leads to the loss of a 
linkage between the sarcolemma and extracellular 
matrix, and this may render muscle fibers more sus- 
ceptible to necrosis or may disrupt the integrity of 
muscle. 
In the past year, three important discoveries have 
been made in the laboratory of Investigator Giinter 
Blobel, M.D., Ph.D. (Rockefeller University). First, 
protein-conducting channels have been shown to 
be gated open by the signal sequence portion of 
the protein that is to be translocated. Thus signal 
sequences function as ligands to open cognate 
protein-conducting channels. Second, bidirectional 
transport of proteins in and out of the nucleus pro- 
ceeds on striking curvilinear tracks that connect in- 
tranuclear transcription and ribonucleoprotein as- 
sembly sites to dedicated nuclear pore complexes. 
Third, two distinct cytosolic fractions have been 
identified for signal sequence-mediated protein 
translocation into the nucleus, one for protein tar- 
geting to the nuclear pore complex and the other for 
translocation through the nuclear pore complex. 
Eukaryotic cells are so named because the genetic 
material (DNA) is separated from the rest of the cell 
by a membranous barrier, the nuclear envelope, that 
restricts the flow of biologic information. Newly syn- 
thesized RNA must pass through this barrier from 
the nucleus, where it is transcribed, to the cyto- 
plasm, where it is translated into protein. Con- 
versely, proteins that are destined to function in the 
nucleus must be imported from their site of synthe- 
sis in the cytoplasm. Many of these proteins affect 
cell growth through transcription, and their entry 
into the nucleus is regulated in response to extracel- 
lular signals. All nucleocytoplasmic transport pro- 
ceeds through channels called nuclear pore com- 
plexes. Proteins within these channels must be able 
to identify and transport only a specific subset of 
cellular proteins and RNAs. The work of Assistant 
Investigator Laura I. Davis, Ph.D. (Duke University) 
and her colleagues is aimed at understanding how 
this process is regulated. They work with yeast cells, 
because although yeast are simple enough to pro- 
vide a genetic system as powerful as in bacteria, they 
follow many of the same rules as do higher eukary- 
otes. Dr. Davis's group has identified several nuclear 
pore complex proteins. Inactivation of one of these 
proteins (NUPI) by mutation showed that it is re- 
quired for RNA export and protein import. They are 
now using both biochemical and genetic ap- 
proaches to identify other proteins involved in this 
process, by virtue of their functional and/or physi- 
cal interaction with NUPI . 
A novel protein kinase encoded by the yeast 
VPS15 gene and a phosphatidylinositol 3-kinase en- 
coded by the VPS34 gene are essential for protein 
sorting to the lysosome-like vacuole in yeast. Ge- 
netic and biochemical characterization of the 
VPS 15 and VPS34 gene products has demonstrated 
that these proteins are components of a membrane- 
associated hetero-oligomeric protein complex. Stud- 
ies by Associate Investigator Scott D. Emr, Ph.D. 
(University of California, San Diego) and his col- 
leagues of the role of this protein kinase and lipid 
kinase complex in regulating intracellular protein 
traffic are beginning to provide new and unex- 
pected insights into the mechanisms governing 
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