Our lab is part of an NIH roadmap center for Nanomedicine. The basic idea of the nanomedicine roadmap centers is to use nanotechnology and other advances in chemistry, structural biology, and cell biology to make advances in medical applications. The center’s focus is protein folding, and in particular protein folding in vivo, i.e. in the presence of chaperones (see my post a few days ago talking about Del Lucent’s work with chaperones in FAH). One can learn more about the center here.
We’re meeting today to present our recent results relevant for protein folding in the nanomed center and to make future plans. FAH has been able to make significant advances in our understanding of how chaperones may work to speed folding, and we’re looking forward to the future where we apply these ideas to specific biomedical applications. In particular, we have a project which we think could (if sucessful) lead to an interesting new drug for cancer. The way this works is that cancer cells need chaperones really badly, as they are growing so quickly. If one can inhibit chaperones, one can kill cancer cells (hopefully without doing too much damage to healthy cells). This approach has been used before, but we hope to use our unique methods to make a major advance in this area.
PS here’s the mission of the nanomed center. I’m reproducing it here to give some better idea of the general goals of the center and to give some idea of what we’re collectively trying to do.
The chaperonin TRiC is a protein folding nanomachine necessary for the
growth of all eukaryotic cells. The protein substrates of this
barrel-shaped 16-subunit nanomachine include actins, tubulins, and
tumor suppressor proteins. Similarly to its archaeal homolog Mm-cpn, it
couples ATP hydrolysis to internalization, folding, and release of
newly synthesized polypeptide chains. The folding cycle includes
opening and closing of a built-in lid of the chaperonin critical for
binding and release.
Our Nanomedicine Development Center (NDC) will
extend and integrate the current techniques in electron cryomicroscopy,
single-molecule imaging, computational biology, and X-ray
crystallography to quantify the chaperonin subunit conformations and
dynamics as well as the protein folding intermediates bound within the
chaperonin cavity. The marriage of these advanced technologies will
allow us to visualize chaperonin machinery functioning not only in
vitro but also within cells.
Building on a more comprehensive and
quantitative description of these protein folding nanomachines, we will
engineer modified chaperonins to provide a novel therapeutic tool for
inhibiting and promoting the folding of selected proteins whose
misfolding or aggregation are associated with human diseases. These
proteins include actin, tumor suppressor proteins p53 and Von Hippel
Lindau, the aggregating A-beta peptide and the cataract related lens
Through visualizing conformations and sites in
which these chains are folded by the chaperonin, together with their
experimentally observed and computed dynamics, we will also design
novel substrates that will be folded efficiently in the naturally
occurring or newly engineered chaperonin, opening new avenues in
protein design. The corresponding approaches will include design of
adaptor peptides for modifying the substrates or chaperonins to enhance
or inhibit substrate-chaperone interactions.
We have assembled a team
of 15 investigators from 6 institutions with expertise in chaperones,
protein folding, electron cryomicroscopy, computer simulation and
modeling, X-ray crystallography, single-molecule imaging and trapping,
and clinical research. We will work together in developing a strategic
set of experimental and computational tools that will enable
characterization of biological nanomachines, both in vitro and in vivo.
We will interact with complementary expertise of other NDC in synthetic
chemistry and fluorescence technologies.
Our Center can be a critical
resource to other NDC who need assistance in solving protein folding
and aggregation problems. Our clinical investigators will contribute to
the design of pilot studies for therapeutic applications in cell
culture models of disease states. We also plan new educational tools
via virtual courses in design and application of biological
nanomachines, aimed at bridging the gap between biology and mechanical
engineering for students in our 6 participating institutions. Finally,
the organization, collaborations and communications in our NDC
exemplify the 21st century goal of conducting interdisciplinary
research via new mechanisms of data sharing and analysis.
For more information, go to the center’s web site at http://proteinfoldingcenter.org/