Multisite Phosphorylation Modulates the T Cell Receptor ζ-Chain Potency but not the Switchlike Response

Mukhopadhyay, Himadri; Wet, Ben de; Clemens, Lara; Maini, Philip K.; Allard, Jacques; Merwe, P. Anton van der; Dushek, Omer

doi:10.1016/j.bpj.2016.03.024

Cited by 24 publications

(57 citation statements)

References 64 publications

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“…S7B). Kinetic proofreading can be realized by a number of different molecular mechanisms, such as sequential or random phosphorylation of the TCR (54,55) and/or the recruitment of Lck-associated coreceptors (56) (SI Appendix, Fig. S7A).…”

Section: Fig 4 Systematic Analyses Of Signaling Models Reveals Thatmentioning

confidence: 99%

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Lever

Lim

Krüger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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141

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T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

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Section: Fig 4 Systematic Analyses Of Signaling Models Reveals Thatmentioning

confidence: 99%

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Lever

Lim

Krüger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

141

View full text Add to dashboard Cite

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“…The strength of this approach is the ability to model with very few assumptions, therefore the qualitative features of our conclusions are expected to be robust to atomistic and chemical details. We anticipate that approaches similar to ours will help reveal complex molecular behavior for other systems, for example cooperativity of binding to unstructured domains of signaling molecules [Mukhopadhyay et al, ].…”

Section: Discussionmentioning

confidence: 99%

Computational simulation of formin‐mediated actin polymerization predicts homologue‐dependent mechanosensitivity

2016

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Many actin structures are nucleated and assembled by the barbed-end tracking polymerase formin family, including filopodia, focal adhesions, the cytokinetic ring and cell cortex. These structures respond to forces in distinct ways. Formins typically have profilin-actin binding sites embedded in highly flexible disordered FH1 domains, hypothesized to diffusively explore space to rapidly capture actin monomers for delivery to the barbed end. Recent experiments demonstrate that formin-mediated polymerization accelerates when under tension. The acceleration has been attributed to modifying the state of the FH2 domain of formin. Intriguingly, the same acceleration is reported when tension is applied to the FH1 domains, ostensibly pulling monomers away from the barbed end. Here we develop a mesoscale coarse-grain model of formin-mediated actin polymerization, including monomer capture and delivery by FH1, which sterically interacts with actin along its entire length. The binding of actin monomers to their specific sites on FH1 is entropically disfavored by the high disorder. We find that this penalty is attenuated when force is applied to the FH1 domain by revealing the binding site, increasing monomer capture efficiency. Overall polymerization rates can decrease or increase with increasing force, depending on the length of FH1 domain and location of binding site. Our results suggest that the widely varying FH1 lengths and binding site locations found in known formins could be used to differentially respond to force, depending on the actin structure being assembled. © 2016 Wiley Periodicals, Inc.

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“…It is widely appreciated that multiple ITAMs contribute to signal amplification with some evidence that they preferentially contribute to enable amplification at low antigen doses . Mathematical models have previously suggested that multiple ITAMs may be important for generating switch‐like responses by various mechanisms, but experimental work has failed to observe this …”

Section: Mechanisms Of T‐cell Sensitivity To Antigenmentioning

confidence: 99%

Molecular mechanisms of T cell sensitivity to antigen

Siller-Farfán

Dushek

2018

Immunological Reviews

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T cells initiate and regulate adaptive immune responses that can clear infections. To do this, they use their T cell receptors (TCRs) to continually scan the surfaces of other cells for cognate peptide antigens presented on major histocompatibility complexes (pMHCs). Experimental work has established that as few 1-10 pMHCs are sufficient to activate T cells. This sensitivity is remarkable in light of a number of factors, including the observation that the TCR and pMHC are short molecules relative to highly abundant long surface molecules, such as CD45, that can hinder initial binding, and moreover, the TCR/pMHC interaction is of weak affinity with solution lifetimes of approximately 1 second. Here, we review experimental and mathematical work that has contributed to uncovering molecular mechanisms of T cell sensitivity. We organize the mechanisms by where they act in the pathway to activate T cells, namely mechanisms that (a) promote TCR/pMHC binding, (b) induce rapid TCR signaling, and (c) amplify TCR signaling. We discuss work showing that high sensitivity reduces antigen specificity unless molecular feedbacks are invoked. We conclude by summarizing a number of open questions.

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Multisite Phosphorylation Modulates the T Cell Receptor ζ-Chain Potency but not the Switchlike Response

Cited by 24 publications

References 64 publications

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Computational simulation of formin‐mediated actin polymerization predicts homologue‐dependent mechanosensitivity

Molecular mechanisms of T cell sensitivity to antigen

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