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OBJECTIVES
Our
research focuses on the processes that mediate and regulate the
movement of membrane proteins throughout cells. In particular we
study the molecular mechanisms that underlie the cell's sorting
machineries responsible for receptor-mediated endocytosis and for
secretion. We also study the question of protein networks; their
regulation and signal-integration linking the spatial organization
of the cortical cytoskeleton in cell with cell migration and growth,
antigen presentation and vesicular traffic.
These efforts led to the first structure determination at atomic
resolution of clathrin. By using X-ray crystalography, we determined
the structure of its amino-terminal portion, a region critical for
interactions controlling coat assembly and cargo sorting. We continued
with this structural approach and determined the mode of interaction
of ß-arrestins and adaptors with clathrin. We also used cryoelectronmicroscopy
to unveil the basic structure of the triskelion leg and established
the way triskelions pack when they form the clathrin coat.
We are currently using biochemical and cell biological approaches
to examine how adaptors recognize the membrane receptors that are
specifically recruited into a clathrin coated pit, and how HIV Nef
activates the endocytosis of the HIV receptor CD4 and MHC class
I, processes that are intimately linked to development of disease.
We recently began focusing on two new research directions for probing
mechanisms in vesicular membrane traffic and protein-protein interactions.
They involve the use of medium throughput screens to identify chemicals
that interfere with membrane traffic (chemical genetics) and the
implementation of a novel Functional Interaction Trap to screen
in complete genomes for specific protein-protein interactions (the
FIT assay).
With these studies we expect to obtain new frameworks for analyzing
some of the molecular contacts and switches that participate in
the regulation, availability, and intracellular traffic of the many
molecules involved in signal transduction, immune responsiveness,
lipid homeostasis and cell-cell recognition. Such biological phenomena
have importance for our understanding of such diseases as cancer,
viral infection, Alzheimer's, as well as other neurological diseases.
MULTIMEDIA
/ IMAGES
MOVIES:
in Quicktime format.
download by right-clicking on "xMB download" and selecting
"Save link as..."
Live-cell imaging of Clathrin-coated pit and coated vesicles formation |
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AP-2 labeled with sigma (symbol)2-EGFP w/ Voice Description
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| 4.9
MB download |
Flourescent LDL as a probe to identify single-endocytic clathrin-coated pits/vesicles |
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Clathrin labeled with EGFP-LCa and LDL labeled with DiI w/ Voice Description
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| 8.9
MB download |
Flourescent
reovirus as a probe to identify
single-endocytic
clathrin-coated pits / vesicles |
Dnm1p
localization and mitochondria constrictions and fissions |
IlLUSTRATIONS:
recently published illustrations; click to open external image viewer.
SELECTED MAGAZINE COVERS:
click each image to view the full-sized cover
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Cell
Volume 95 Number 4 |
CMLS
Volume 54 Number 3 |
Current
Biology
Volume 9 Number 4 |
Nature
Volume 418 Issue 6901 |
Current
Opinion in Immunology
Volume 15 Issue 5 |
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Molecular
Biology of the Cell
Volume 15 |
Nature
Volume 432 Issue 7017 |
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