Absolute Ligand Discrimination by Dimeric Signaling Receptors

Fathi, Sepehr; Nayak, Chitra R.; Feld, Jordan J.; Zilman, Anton

doi:10.1016/j.bpj.2016.07.029

Cited by 10 publications

(17 citation statements)

References 23 publications

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“…To clarify how SIPC transduces such bimodal responses at the molecular level, one would need to identify its endogenous receptor in A. amphitrite. Although complex ligand-receptor responses, dependent on receptor expression, have been recently documented in other cellular systems (Jenni et al, 2015;Fathi et al, 2016), the absence of the genomic sequence of A. amphitrite and the limited available transcriptomic data make any attempt to explain at the molecular level the bimodal response of cyprids to SIPC highly speculative, at present.…”

Section: Discussionmentioning

confidence: 99%

Should I stay or should I go? The settlement-inducing protein complex guides barnacle settlement decisions

Kotsiri

Protopapa

Mouratidis

et al. 2018

Journal of Experimental Biology

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Reproduction in barnacles relies on chemical cues that guide their gregarious settlement. These cues have been pinned down to several sources of settlement pheromones, one of which is a protein termed settlement-inducing protein complex (SIPC), a large glycoprotein acting as a pheromone to induce larval settlement and as an adhesive in surface exploration by the cyprids. Settlement assays in laboratory conditions with Amphibalanus (=Balanus) amphitrite cyprids in the presence of SIPC showed that cyprids exhibit settlement preference behaviour at lower concentrations of SIPC [half maximal effective concentration (EC 50)=3.73 nmol l −1 ] and settlement avoidance behaviour at higher concentrations (EC 50 =101 nmol l −1). By using truncated fragments of SIPC in settlement assays, we identify that domains at the N-terminus of SIPC transduce settlement preference cues that mask the settlement avoidance cues transduced by domains at its C-terminus. Removing the N-terminal 600 amino acids from SIPC resulted in truncated fragments that transduced only settlement avoidance cues to the cyprids. From the sexual reproduction point of view, this bimodal response of barnacles to SIPC suggests that barnacles will settle gregariously when conspecific cues are sparse but will not settle if conspecific cues inform of overcrowding that will increase reproductive competition and diminish their reproductive chances.

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Section: Discussionmentioning

confidence: 99%

Should I stay or should I go? The settlement-inducing protein complex guides barnacle settlement decisions

Kotsiri

Protopapa

Mouratidis

et al. 2018

Journal of Experimental Biology

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“…Many aspects of IFN signaling are captured by the relatively simple equilibrium description of receptor complex formation obtained from the steady state of our ODE model, providing qualitative insight into how various components of this system affect signaling dynamics. The equilibrium solution for the number of active ternary complexes formed in response to a ligand can be found by solving the chemical kinetic equations along with the detailed balance condition K 1 K 3 = K 2 K 4 (see below), where K 1 and K 2 are the equilibrium dissociation constants for IFN binding to each of IFNAR1 and IFNAR2, and K 4 and K 3 are the in-membrane dissociation constants for recruitment of IFNAR1 and IFNAR2 respectively to the ternary complex (see Figure 1A) (53). The result is an expression for the equilibrium number of ternary complexes (53,65):…”

Section: Mathematical Methodsmentioning

confidence: 99%

“…Signaling systems with crosstalk must decouple ligand concentration from ligand affinity in the downstream response if functional plasticity is to be achieved. We refer to such a decoupling as absolute discrimination (53,54). In systems with absolute discrimination, functional differences can only be partially compensated by changes in ligand concentration.…”

Section: Introductionmentioning

confidence: 99%

“…Cellular responses that require receptor activation above this threshold are consequently specific to high affinity ligands. One proposed mechanism for affinity-dependent receptor saturation relies on the nonmonotonic nature of the dose-response curve of dimeric receptors (53,55). Kinetic proofreading and its enhanced version know as adaptive sorting, studied in the context of T cell receptor sensing, also demonstrate affinity-dependent saturation (54,56).…”

Section: Introductionmentioning

confidence: 99%

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Determinants of Ligand Specificity and Functional Plasticity in Type I Interferon Signaling

et al. 2021

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The Type I Interferon family of cytokines all act through the same cell surface receptor and induce phosphorylation of the same subset of response regulators of the STAT family. Despite their shared receptor, different Type I Interferons have different functions during immune response to infection. In particular, they differ in the potency of their induced anti-viral and anti-proliferative responses in target cells. It remains not fully understood how these functional differences can arise in a ligand-specific manner both at the level of STAT phosphorylation and the downstream function. We use a minimal computational model of Type I Interferon signaling, focusing on Interferon-α and Interferon-β. We validate the model with quantitative experimental data to identify the key determinants of specificity and functional plasticity in Type I Interferon signaling. We investigate different mechanisms of signal discrimination, and how multiple system components such as binding affinity, receptor expression levels and their variability, receptor internalization, short-term negative feedback by SOCS1 protein, and differential receptor expression play together to ensure ligand specificity on the level of STAT phosphorylation. Based on these results, we propose phenomenological functional mappings from STAT activation to downstream anti-viral and anti-proliferative activity to investigate differential signal processing steps downstream of STAT phosphorylation. We find that the negative feedback by the protein USP18, which enhances differences in signaling between Interferons via ligand-dependent refractoriness, can give rise to functional plasticity in Interferon-α and Interferon-β signaling, and explore other factors that control functional plasticity. Beyond Type I Interferon signaling, our results have a broad applicability to questions of signaling specificity and functional plasticity in signaling systems with multiple ligands acting through a bottleneck of a small number of shared receptors.

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“…Innate interferon signals are sensed by the cells through heterodimeric receptors which are capable of absolute ligand discrimination . Receptor‐associated kinases tyrosine‐phosphorylate the transcription factors STAT1 and STAT2, triggering heterodimer formation.…”

Section: Heterogeneous Expression Of Interferon‐stimulated Genesmentioning

confidence: 99%

Antiviral interferon response at single‐cell resolution

Talemi

Höfer

2018

Immunological Reviews

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Experimental studies of the innate immune response of mammalian cells to viruses reveal pervasive heterogeneity at the level of single cells. Interferons are induced only in a fraction of virus-infected cells; subsequently a fraction of cells exposed to interferons upregulate interferon-stimulated genes. Nevertheless, quantitative experiments and linked mathematical models show that the interferon response can be effective in curbing viral spread through two distinct mechanisms. First, paracrine interferon signals from scattered source cells can protect many uninfected cells, and the self-amplification of interferon production might serve to calibrate response amplitude to strength of viral infection. Second, models of the tug-of-war between viral replication and the innate interferon response imply a pivotal role of interferon action on already infected cells in curbing viral spread, through effectively lowering virus replication rate. This finding is in line with the observation that several pathogenic viruses selectively abrogate interferon action on infected cells. Thus, interferons may delay viral spread in acute infections by acting as sentinels, warning uninfected cells of imminent danger, or as negative feedback regulators of virus replication in infected cells. The timing of the interferon response relative to the onset of viral replication is critical for its effectiveness in curbing viral spread.

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Absolute Ligand Discrimination by Dimeric Signaling Receptors

Cited by 10 publications

References 23 publications

Should I stay or should I go? The settlement-inducing protein complex guides barnacle settlement decisions

Should I stay or should I go? The settlement-inducing protein complex guides barnacle settlement decisions

Determinants of Ligand Specificity and Functional Plasticity in Type I Interferon Signaling

Antiviral interferon response at single‐cell resolution

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