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Ligand detection and discrimination by spatial relocalization: A kinase-phosphatase segregation model of TCR activation
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Burroughs, Nigel John, Lazic, Zorana and van der Merwe, P. Anton (2006) Ligand detection and discrimination by spatial relocalization: A kinase-phosphatase segregation model of TCR activation. Biophysical Journal, Vol.91 (No.5). pp. 1619-1629. doi:10.1529/biophysj.105.080044 ISSN 0006-3495.
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Official URL: http://dx.doi.org/10.1529/biophysj.105.080044
Abstract
We develop a model of tyrosine phosphorylation and activation of the T-cell receptor (TCR) by localization to regions of close membrane-membrane proximity ( close contact) that physically exclude tyrosine phosphatases such as CD45. Phosphatase exclusion generates regions of low phosphatase and high kinase activity and thus our model provides a framework to examine the kinetic segregation model of TCR activation. We incorporate a sequence of activation steps modeling the construction of the signalosome with a final sequestered, or high-stability, signaling state. The residence time of unbound TCRs in tyrosine kinase-rich domains is shown to be too short for accumulation of activation steps, whereas binding to an agonist lengthens the localization time and leads to generation of fully active TCRs. Agonist detection depends only on this localization, and therefore kinetic segregation represents a viable ligand detection mechanism, or signal transduction mechanism across membranes, distinct from receptor oligomerization and conformational change. We examine the degree of discrimination of agonists from a background of null ( self) peptides, and from weak agonists achievable by this mechanism.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QH Natural history > QH301 Biology | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Mathematics Faculty of Science, Engineering and Medicine > Research Centres > Warwick Systems Biology Centre |
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| Journal or Publication Title: | Biophysical Journal | ||||
| Publisher: | Cell Press | ||||
| ISSN: | 0006-3495 | ||||
| Official Date: | 1 September 2006 | ||||
| Dates: |
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| Volume: | Vol.91 | ||||
| Number: | No.5 | ||||
| Number of Pages: | 11 | ||||
| Page Range: | pp. 1619-1629 | ||||
| DOI: | 10.1529/biophysj.105.080044 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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