[Phys-seminars] 2011-08-31 Special physics seminar

physics at bgu.ac.il physics at bgu.ac.il
Tue Aug 16 11:52:09 IDT 2011

Special physics seminar

  DATE: 31-08-2011

  TIME: 12:00 (noon)

  PLACE: Physics building (#54) room 207

Studying mechanisms of immune cell activation at the single molecule level

Eilon Sherman, Ph.D, Laboratory of Cellular and Molecular Biology, CCR, NCI, NIH, Bethesda, MD

Cells transduce information across their plasma membrane via engagement
of surface receptors and the subsequent recruitment of intracellular
proteins to these receptors. These out-of-equilibrium molecular systems
often result in the formation of transient, heterogeneous protein complexes
and macro-molecular clusters that serve to amplify, relay and regulate the
incoming signals (much like hubs in a telecommunication system). 
Although these signaling structures play a crucial role in health and disease,
including immune activation, cancer, and HIV infection, the detailed biophysical 
mechanisms by which they assemble and serve to activate cells remain poorly understood 
due to shortcomings in current research techniques.

We have developed and applied two-color photoactivated localization microscopy (PALM)
to study the organization, structure and function of signaling complexes in the activation
of immune (T) cells, at the single molecule level. Using this method,
individual molecules can be identified and localized with resolution down to ~20nm.
Second-order and clustering statistics were applied to resolve size-distributions of
signaling complexes and molecular interactions at the plasma membrane of the cells.
Our results show that nanoclusters, signaling complexes as small as dimers and trimers,
govern the earliest events of T cell activation through dynamic interactions.
Importantly, we show that these signaling complexes assume, in several ways, novel patterns of
nanoscale organization that are crucial for cell activation. Taking a multidisciplinary approach, 
including the use of genetic mutagenesis, targeted drugs, statistical analysis and Monte-Carlo simulations,
we could trace mechanisms that govern the formation of these patterns. Such mechanisms include combinations
of dynamic protein-protein and protein-lipid interactions, hop-diffusion, confinement and patterning by the
cell cytoskeleton and plasma membrane. These results extend our understanding of the mechanism of immune cell activation,
findings also relevant to other receptor systems.

I will further discuss novel research techniques that we have developed to better study critical signaling pathways in live
interacting cells and in molecular detail.

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