A molecular cage. Image: UCLA
University of California, Los
Angeles (UCLA) biochemists have designed specialized
proteins that assemble themselves to form tiny molecular cages hundreds of
times smaller than a single cell. The creation of these miniature structures
may be the first step toward developing new methods of drug delivery or even
designing artificial vaccines.
“This is the first decisive
demonstration of an approach that can be used to combine protein molecules
together to create a whole array of nanoscale materials,” said Todd
Yeates, a UCLA professor of chemistry and biochemistry and a member of the UCLA–DOE
Institute of Genomics and Proteomics and the California NanoSystems Institute
Published in Science, the research could be used to create cages from any number
of different proteins, with potential applications across the fields of
medicine and molecular biology.
UCLA graduate student Yen-Ting Lai, lead
author of the study, used computer models to identify two proteins that could
be combined to form perfectly shaped 3D puzzle pieces. Twelve of these
specialized pieces fit together to create a molecular cage a mere fraction of
the size of a virus.
“If you just connect two random
proteins together, you expect to get an irregular network,” said Yeates,
senior author of the study. “In order to control the geometry, the idea
was to make a rigid link holding the two proteins in place as if they were
parts of a toy puzzle.”
The specifically designed proteins intermesh
to form a hollow lattice that could act as a vessel for drug delivery, he said.
“In principle, it would be possible to
attach a recognition sequence for cancer cells on the outside of the cage, with
a toxin or some other ‘magic bullet’ contained inside,” said Yeates.
“That way, the drug could be delivered directly to certain targets like
At this stage, the assembled protein cages
are porous enough that a drug placed inside would likely leak out during the
delivery process, Lai said. His next project will involve constructing a new
molecular cage with an interior that will be better sealed.
Another use for the versatile protein
structures might be as artificial vaccines. Some traditional vaccines use an
inactive surface protein from a virus to trick the body’s immune system into
thinking it is under attack. This method isn’t always effective, because
sometimes the protein in question doesn’t look enough like the virus to trigger
a strong response from the body’s defenders.
However, by decorating the surface of a
molecular cage with segments of virus-derived proteins, the tiny structures
might better mimic a virus, stimulating an immune response even stronger than a
traditional vaccine and better protecting the human recipient from illness.
Before these protein structures can be used
in medical applications, the molecular containers themselves must be
constructed from human-like proteins, rather than the currently employed
bacterial proteins that the human body might immediately clear from
circulation, Yeates said.
“Our first challenge will be repeating
these kinds of designs with molecules that are less likely to generate a host
immune response,” he said. “Generally, we want to use proteins that
look like human proteins so the body does not recognize them as foreign.”
The idea of building complex, self-assembled
protein structures has been Yeates’ ambition since he published a paper
outlining preliminary work on this method in 2001. Yet the concept remained on
the back burner for 10 years until Yen-Ting Lai joined Yeates’ research group.
With three master’s degrees—in structural biology, bioinformatics, and biomedical
engineering—Lai had the right combination of skills to bring the research to
fruition, Yeates said.
This project is federally funded by the
National Science Foundation. Other coauthors include UCLA senior staff
scientist Duilio Cascio.
A second paper
co-authored by Yeates creates similarly designed molecular cages using multiple
copies of the same protein as building blocks. The scientists control the shape
of the cage by computing the sequence of amino acids necessary to link the
proteins together at the correct angles. The research, also published today in
Science, resulted from a collaboration between the UCLA team and professor
David Baker at the University
This alternative method represents a more
versatile approach because it requires only one type of protein to form a
structure, Yeates said. However, devising different kinds of links between the
identical proteins remains a major challenge. Lead author Neil King, a
postdoctoral scholar at the University
of Washington and a
former student of Yeates, took the numerous computer-generated possibilities
and tested each version experimentally until he found one which produced the
Filed Under: Drug Discovery