|
Laura Segatori
Research Group
|
|
|
Laura Segatori
T.N. Law Assistant Professor in Chemical and Biomolecular Engineering
Research Interests:
Biotechmology and Protein Engineering
Cell and Tissue Engineering
Protein Folding
Neurodegenerative Diseases
Education:
Postdoctoral Research Associate (2005-2007), The Scripps
Research Institute
Ph.D. in Chemical Engineering (2005), University of Texas at Austin
Laurea in Biotechnology (2000), University of Bologna, Italy
The flexibility of the polypeptide backbone, combined with
the multitude of non-covalent interactions established by amino
acid side chains, allows a protein to assume a variety of three-dimensional
conformations. Failures of the folding mechanisms to assist in
the formation of native protein conformations results in the
accumulation of dysfunctional or unstable protein structures;
trace amounts of aggregates may also occur spontaneously especially
during aging. Therefore, a delicate balance between two main
protective strategies –- the repair of damaged proteins
and their selective degradation - has evolved in all organisms.
Complex interactions among molecular effectors of the chaperone
and degradation systems maintain this homeostatic equilibrium
in eukaryotic cells. These
are commonly referred to as protein quality control processes
(QC). QC is developed to assist the folding of newly synthesized
proteins and refold or degrade polypeptides that fail to attain
or maintain a native structure. Its proper function is crucial
in preventing the deposition of aggregation-prone, misfolded
polypeptides associated with degenerative disorders, such as
Alzheimer's and Parkinson diseases.
The intra- or extracellular accumulation of aggregated proteins –-
whose identity determines the specific clinical manifestations –-
and the formation of highly ordered fibrils have recurrently
been
associated to neurodegeneration and amyloid diseases. The molecular
determinants that cause a protein state to be predisposed to
aggregation have not been completely determined. However, evidence
exists for an underlying link between impairment of protein folding
and the formation of dysfunctional, aggregation prone proteins.
In physiologic conditions, such cellular malfunctions are rescued
by protective cellular systems, namely chaperones and degradation
systems. It is therefore proposed that mutations that cause accumulation
of misfolded proteins, or age related collapse of QC, alter the
delicate balance between the cellular chaperones and the degradation
systems.
My research interests focus on the relationship between protein
folding and disease, the molecular determinants of cellular protein
folding, and on the development of protein engineering strategies
to enhance cellular chaperone and/or degradation systems. Our
goals are to obtain a broader understanding of the molecular mechanisms
involved in cellular protein folding, and to develop methods for
manipulating eukaryotic cells, which can be used for therapeutic
applications.
Modified 09/28/2009
Selected Publications
-
Segatori, L., Arredondo, S., Gilbert, H. F., and Georgiou, G. De novo Design and Evolution of Artificial Disulfide Isomerase Enzymes Analogous to the Bacterial DsbC. J Biol Chem, in press.
-
Mu, T., Ong, D. S., Wang, Y., Balch, W. E., Yates, J. R., Segatori, L. and Kelly, J. W. Proteostasis Regulators and Pharmacologic Chaperones Synergize to Restore Protein Homeostatis in Loss-of-Function Diseases. Cell, in press (Sept 5, 2008).
-
Segatori, L., Murphy, L., Arredondo, S., Johnston, K., Kadokura, H., Gilbert, H. F., Beckwith, J., and Georgiou, G. Conserved role of the linker a-helix of the bacterial disulfide isomerase DsbC in the avoidance of misoxidation by DsbB. J. Biol Chem 2006 Feb 24;281(8):4911-9.
-
Georgiou, G. and Segatori, L. Preparative expression of secreted proteins in bacteria: status report and future prospects. Curr Opin Biotechnol. 2005 Oct; 16(5):538-45. Review.
-
Zhang, M., Monzingo, A. F., Segatori, L., Georgiou, G. and Robertus, J. D. Structure of DsbC from Haemophilus influenzae. Acta Crystallogr D Biol Crystallogr. 2004 Sep;60(pt9):1512-8.
-
Segatori, L., Paukstelis, P. J., Gilbert, H. F., and Georgiou, G. Engineered DsbC chimeras catalyze both protein oxidation and disulfide-bond isomerization in Escherichia coli: Reconciling two competing pathways. Proc Natl Acad Sci U S A. 2004 Jul 06;101(27):10018-23.
Modified 8/4/2008
|
|
