A New Mechanism for Initial Activation of T-Cell Receptors

BPJ_108_10.c1.inddQ. How did you compose this image?

The image corresponds to a snapshot from a long molecular dynamics simulation of the cytoplasmic CD3 epsilon chain embedded in a liquid-ordered, liquid-disordered membrane domain mimic. Pre-rendering was done using the VMD visualization package (http://www.ks.uiuc.edu/Research/vmd/) and posteriorly rasterized using the Blender rendering software (https://www.blender.org).

Q. How does this image reflect your scientific research?

The main drive of our research is to understand the molecular details of the immunological response. To be more precise, we aim to understand the molecular mechanism by which the T-cell receptor (TCR) engagement triggers the response in the cell. It is generally accepted that the cascade is amplified by the phosphorylation of tyrosine residues localized in the cytoplasmic domains of the receptor. Here, we used a coarse-grained model (using the widely used MARTINI model) to understand the molecular mechanism by which these tyrosines are activated. We use the CD3 epsilon chain as a model system. In the resting state (not activated), the protein is localized close to the liquid-disorder membrane domain. Moreover, the tyrosines are deeply hidden in the hydrophobic regions of the membrane. The equilibrium, however, can be modulated by the presence of a facilitator molecule (e.g., ganlgioside), driving the configuration into the liquid-ordered domain and exposing the cytoplasmic domain and tyrosines to the surface. This study highlights the critical role of the membrane and its composition during the TCR activation.

We hypothesize that the basic ideas are translatable to other ITAM bearing receptors (BCR, Fc Receptors) and to Receptor Tyrosine Kinases that have unstructured cytoplasmic tails with tyrosine phosphorylation sites.  For example, Stuart McLaughlin proposed electrostatic interactions control the accessibility of the EGFR tail (J. Gen Physiology 2005; Biophysical J. 2009).

 Q. Can you please provide a few real-world examples of your research?

Membrane domains play key roles in a variety of cellular processes. One example is in host-pathogen interactions. It has been shown that several viruses, including HIV, require the presence of rich cholesterol domains in order for internalization to proceed. Other pathogens like Vibrio cholera make use of gangliosides-rich domains in order to internalize their toxins.

The involvement of membrane domains has been cited in many different aspects of the immune system.  There has been long- standing debate regarding their roles in immunoreceptor activation, which are challenging to validate experimentally.

 Q. How does your research apply to those who are not working in your specific field?

This collaborative project was first conceived by brainstorming sessions of our modeling team from the Center for Nonlinear Studies (Los Alamos National Laboratory) with cell biologists and signaling experts at the New Mexico Spatio Temporal Modeling Center (STMC; at the University of New Mexico). As you may expect, researches from different fields (immunologists, engineers, physicists, chemists, biologists) were providing inputs and clarifying doubts during our extensive meetings. The experimentalists are now trying to validate (or invalidate) the predictions of the model. This back-and-forth process will be useful for refining the models. So, in summary, it takes an interdisciplinary group to tackle these kinds of big problems.

 Q. Do you have a website where our readers can view your recent research?

For more details of our work, people can refer to:

http://cnls.lanl.gov/External/

http://stmc.health.unm.edu

https://newmexicoconsortium.org/

– Cesar A. López, Anurag Sethi, Byron Goldstein, Bridget S. Wilson, S. Gnanakaran

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s