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Introduction

The dimerization of the extracellular receptor domains is a important necessity for the functionality of our modular receptor system. Presenting the system a stimulus in the form of spatial arranged ligands, the extracellular domains dimerize, thus the corresponding intracellular parts such as the split lactamase halves or split fluorescent proteins complement to measureable output. To analyse the theoretical functionality due to dimerization, first two receptor dimerization models (one T cell receptor model and one general receptor model) are introduced and discussed and then a proper model for the modular receptor system is constructed.

T cell receptor dimerization model I

T cells are a special type of white blood cells (lymphocytes) and play a central role in cell-mediated immunity. They carry special receptors, so called T cell receptors (TCR) on their membrane. One part of the mechanisms to activate a TCR and thus to activate a T Cell is the binding of a ligand, also called antigen, to the TCR. As research showed, one single ligand-TCR complex does not lead to a T cell response yet, as at least two ligand-TCR complexes and their dimerization seem to be required for proper T cell activation (Schamel, 2006; Bachmann 1999). In our case the ligands are nitro-iodo-phenol (NIP) molecules attached to a DNA-Origami structure at a (variable) distance of ~6nm to each other. These NIPs are recognized and bound by the TCRs. As the distance is small enough for two TCRs to approach very closely when each of them binds a NIP, they can dimerize.

Extracellular signaling

A simplified pathway shows the extracellular sequence of TCR activation. After the NIP binding two complexes come together and form a dimer which then leads to activaton of the TCR and further intracellular signaling and T cell activation.

Figure 1 : Pathway of TCR dimerization

Reaction kinetics

The T cell maintains a pool of TCRs (T) which is dynamic. The continuous de novo expression, random internalization and degradation runs with constant rate S :

One NIP molecule (N) binds to a TCR (T) with the reaction rate k_on or a TCR-NIP complex (TN) dissociates with the reaction rate k_off :

Two TCR-NIP (TN) complexes dimerize to a TCR-NIP dimer (TND) with rate k_don ; the dissociation of a TCR-NIP dimer runs with rate k_doff :

In order to get active TCRs, the TCR-NIP dimer (TND) has to switch into two active TCRs (A) with rate k_a :

After activation, the TCR is internalised with rate k_i and does not take part anymore in the extracellular signaling :

ODEs derived from the kinetics (Details)

In the following equation T represents the free TCR in the T cell membrane where k_eff is a combination of k_don, k_doff and k_a. k_I is k_on/k_off :


The equation for the active TCR A is shown in the following:

TCR activity for a set of parameters

The two ODEs above of this first basic model for a set of parameters are solved numerically. They reveal the timecourse of the TCR activity aswell as the one of the unbound TCR.

80%	chosen parameters: s = 0.1;  % turnover rate kon = 1;  % TCR-NIP binding rate koff = 0.2;  % TCR-NIP dissociating rate kdon = 1;  % TCR-NIP dimerization rate kdoff = 0.2;  % dimer dissociating rate ka = 1;  % activation rate ki = 0.8;  % internalization rate N = 0.2;  % NIP amount initial integration conditions: T0 = 1  % free TCR density TA0 = 0;  % active TCR density

Extensions: Ultrasensivity and biphasic kinetics

Ultrasensitivity

The kinetics of the TCR activation can be generalised by substituting the second order kinetic of the ligand N and the receptor T by a parameter h, which then represents the kinetical order of the system.


Now the sensitivity of the model to ligand and receptor is altered aswell. It increases when the kinetical order increases. For a high kinetic order, small changes in ligand N or receptor T cause big changes in the TCR activation (A). Generally h can be described as:
This logarithmic sensitivity means that the increasing of the concentration of N with 10% will lead to an increase in the rate of TCR activation of 10000% for the 4th order kinetic (h=4).