Cooperative Clustering Digitizes Biochemical Signaling and Enhances its Fidelity

Roob, Edward; Trendel, Nicola; Wolde, Pieter Rein ten; Mugler, Andrew

doi:10.1016/j.bpj.2016.02.031

Cited by 27 publications

(23 citation statements)

References 36 publications

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“…On average clusters consisted of around 13 molecules. Incidentally, this cluster size is very similar to the size of clusters providing optimal fidelity in digital signalling as reported in a theoretical study31. For higher Ca 2+ concentrations, [Ca 2+ ] i ≈ 20 μM, and after long exposure to an increased Ca 2+ concentration, the mean number of molecules in a cluster was essentially the same as for the lower Ca 2+ concentration (Fig.…”

Section: Resultssupporting

confidence: 86%

C2-domain mediated nano-cluster formation increases calcium signaling efficiency

Bonny

Hui

Schweizer

et al. 2016

Sci Rep

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Conventional protein kinase Cs (cPKCs) are key signaling proteins for transducing intracellular Ca2+ signals into downstream phosphorylation events. However, the lifetime of individual membrane-bound activated cPKCs is an order of magnitude shorter than the average time needed for target-protein phosphorylation. Here, we employed intermolecular Förster resonance energy transfer (FRET) in living cells combined with computational analysis to study the spatial organization of cPKCs bound to the plasma membrane. We discovered Ca2+-dependent cPKC nano-clusters that significantly extend cPKC’s plasma-membrane residence time. These protein patterns resulted from self-assembly mediated by Ca2+-binding C2-domains, which are widely used for membrane-targeting of Ca2+-sensing proteins. We also established clustering of other unrelated C2-domain containing proteins, suggesting that nano-cluster formation is a key step for efficient cellular Ca2+-signaling.

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Section: Resultssupporting

confidence: 86%

C2-domain mediated nano-cluster formation increases calcium signaling efficiency

Bonny

Hui

Schweizer

et al. 2016

Sci Rep

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“…Dynamic molecular clusters can form through weak binding interactions between multivalent molecules. They are highly plastic structures with a distribution of stoichiometries and sizes; they are becoming increasingly recognized as molecular platforms to drive key cellular functions, especially receptor-mediated signaling (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). For example, the epidermal growth factor receptor (EGFR) dimerizes and develops kinase activity when it binds its ligand, resulting in multiple phosphorylated sites on the cytoplasmic domains; these in turn interact with multiple SH2 domains on other multivalent scaffold or adaptor proteins, which then recruit additional binding partners (13).…”

Section: Introductionmentioning

confidence: 99%

The interplay of structural and cellular biophysics controls clustering of multivalent molecules

Chattaraj

Youngstrom

Loew

2018

Preprint

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Dynamic molecular clusters are assembled through weak multivalent interactions and are platforms for cellular functions, especially receptor-mediated signaling. Clustering is also a prerequisite for liquidliquid phase separation. But it is not well understood how molecular structure and cellular organization control clustering. Using coarse-grain kinetic Langevin dynamics, we performed computational experiments on a prototypical ternary system modeled after membrane-bound nephrin, the adaptor Nck1 and the actin nucleation promoting factor NWASP. Steady state cluster size distributions favored stoichiometries that optimized binding (stoichiometry matching), but still were quite broad. At high concentrations, the system can be driven beyond the saturation boundary such that cluster size is limited only by the number of available molecules. This behavior would be predictive of phase separation. Domains close to binding sites sterically inhibited clustering much less than terminal domains because the latter effectively restrict access to the cluster interior. Increased flexibility of interacting molecules diminished clustering by shielding binding sites within compact conformations. Membrane association of nephrin increased the cluster size distribution in a density-dependent manner. These properties provide insights into how molecular ensembles function to localize and amplify cell signaling.

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“…However, these studies showed that Ras dimerization activates the MAPK pathway and therefore likely plays an important role in signal transduction. Similarly, a role for dimerization and nanocluster formation in signaling (Solman et al, 2015;Roob et al, 2016), possibly due to orientation changes of the G-domain (Mazhab-Jafari et al, 2015), was also reported by other groups. Specifically, Muratcioglu et al (2015) reported that K-Ras dimer formation is nucleotide dependent using dynamic light scattering and nuclear magnetic resonance (NMR) spectroscopy.…”

Section: Membrane Binding Of Rasmentioning

confidence: 67%

Common mechanisms of catalysis in small and heterotrimeric GTPases and their respective GAPs

Gerwert

Mann

Kötting

2017

Biological Chemistry

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GTPases are central switches in cells. Their dysfunctions are involved in severe diseases. The small GTPase Ras regulates cell growth, differentiation and apoptosis by transmitting external signals to the nucleus. In one group of oncogenic mutations, the 'switch-off' reaction is inhibited, leading to persistent activation of the signaling pathway. The switch reaction is regulated by GTPase-activating proteins (GAPs), which catalyze GTP hydrolysis in Ras, and by guanine nucleotide exchange factors, which catalyze the exchange of GDP for GTP. Heterotrimeric G-proteins are activated by G-protein coupled receptors and are inactivated by GTP hydrolysis in the Gα subunit. Their GAPs are called regulators of G-protein signaling. In the same way that Ras serves as a prototype for small GTPases, Gα i1 is the most well-studied Gα subunit. By utilizing X-ray structural models, time-resolved infrared-difference spectroscopy, and biomolecular simulations, we elucidated the detailed molecular reaction mechanism of the GTP hydrolysis in Ras and Gα i1 . In both proteins, the charge distribution of GTP is driven towards the transition state, and an arginine is precisely positioned to facilitate nucleophilic attack of water. In addition to these mechanistic details of GTP hydrolysis, Ras dimerization as an emerging factor in signal transduction is discussed in this review.

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Cooperative Clustering Digitizes Biochemical Signaling and Enhances its Fidelity

Cited by 27 publications

References 36 publications

C2-domain mediated nano-cluster formation increases calcium signaling efficiency

C2-domain mediated nano-cluster formation increases calcium signaling efficiency

The interplay of structural and cellular biophysics controls clustering of multivalent molecules

Common mechanisms of catalysis in small and heterotrimeric GTPases and their respective GAPs

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