Adaptor proteins: Flexible and dynamic modulators of immune cell signalling

Borowicz, P. P.; Chan, Hanna; Hauge, Anette; Spurkland, Anne

doi:10.1111/sji.12951

Cited by 16 publications

(18 citation statements)

References 263 publications

(490 reference statements)

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“…A simple definition is that adaptor proteins "facilitate signal transduction through interactions with other proteins" (Borowicz et al 2020;Langeberg and Scott 2015). Such a function was shown for Slam through the necessity for the recruitment and the verification of direct binding of RhoGEF2, a regulator of the Rho-Rok pathway (Wenzl et al 2010) Adaptor proteins facilitate the right localization of their binders and to fulfil that task they need certain qualities (Borowicz et al 2020;Langeberg and Scott 2015): binding domains, binding motifs and structural flexibility. A PDZ-binding motif and an SH3-binding motif have been identified for the recruitment of (at least) RhoGEF2 (PDZ), Patj (PDZ) and Cindr (SH3).…”

Section: Slam As Adaptormentioning

confidence: 99%

“…The high intrinsic disorder suggests a great structural flexibility of Slam protein, a feature which is highly relevant for adaptors. This is (among other things) because they can easily be post-translationally modified, the disorder enables flexible links between structured domain and binding sites, it makes dynamic structure changes possible, it increases the hydrodynamic radius of the protein and promotes oligomerization (Borowicz et al 2020;Iakoucheva 2004;Houtman et al 2006;Hofmann et al 2012;Cortese, Uversky, and Keith Dunker 2008).…”

Section: Slam As Adaptormentioning

confidence: 99%

“…Figure37"Schematic overview of hypothetical models presenting functions of adaptor proteins", picture adapted from(Borowicz et al 2020). Scientific results concerning Slam all point towards a possible adaptor function during Drosophila cellularization.…”

mentioning

confidence: 99%

“…(Borowicz et al 2020). Slams function during Drosophila development follows a strong spatiotemporal regulation, which suggest a flexibility in interaction and function.…”

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confidence: 99%

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Biochemical Analysis of Slam – a polarity protein during early Drosophila embryogenesis

Stephanie¹

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First, I would like to express my gratitude to Prof. Dr. Jörg Großhans who gave me the opportunity for my doctoral studies. His guidance, patience, and encouragement during the time of research and writing was elementary for the success of this thesis. I would like to thank my thesis committee members Prof. Dr. Ralf Ficner and Prof. Dr. Heike Krebber. Thank you for investing the time and your helpful comments and support. The different perspective on my work was most helpful. I would like to acknowledge my colleagues for their help and insightful discussions. My special thanks go to my immediate team Dr. Sreemukta Acharya and Dr. Shuling Yan, who would answer any Slam-related question and did the groundwork to this study. I truly missed you in the lab Mukta! I thank Dr.

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Section: Slam As Adaptormentioning

confidence: 99%

Section: Slam As Adaptormentioning

confidence: 99%

mentioning

confidence: 99%

“…(Borowicz et al 2020). Slams function during Drosophila development follows a strong spatiotemporal regulation, which suggest a flexibility in interaction and function.…”

mentioning

confidence: 99%

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Biochemical Analysis of Slam – a polarity protein during early Drosophila embryogenesis

Stephanie¹

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“…SLP65 [112] and SLP75 [113] are crucial signaling proteins involved in BCR and TCR signal transduction, respectively. In principle, signaling is achieved by complex protein networks [114], however BCR and TCR signaling are now seen in the light of phase separation [115]. Phase separation of adapter proteins in immune cells has been demonstrated in T cells [46,53,87] and in B cells [116].…”

Section: The Need For Simulationsmentioning

confidence: 99%

Biophysical characterization and computational modeling of phase separation of immune adapter proteins

Maier¹

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The processes of B cell activation and development are stimulated by antigen binding to the B cell receptor. Pre-signaling clusters are present in unstimulated, resting B cells and assemble by tripartite phase separation of two signaling adapter proteins, SLP65 and CIN85, and intracellular VAMP7-positive vesicles. The pre-signaling clusters of the B cell receptor signaling pathway are required for the adaptive immune response. A compromised humoral immune response has been reported in patients where SLP65 or CIN85 malfunction. Also, B cell culture studies show that pre-signaling clusters are required for an intracellular Ca 2+ response. Thus, phase separation of these proteins in B cells seems to be functionally relevant.In order to dissect the thermodynamics of phase separation of SLP65 and CIN85, we determined the affinities of the binding modules, i.e. the proline rich motifs (PRMs) and the SH3 domains individually and modelled it with an appropriate program.Before this study, the binding preferences and number of relevant binding modules were unknown. Three SH3 domains of each CIN85 monomer that forms a trimer bind to a number of PRMs of SLP65. First, the promiscuous binding of the three SH3 domains of CIN85 to seven potential PRMs of SLP65 was disentangled on the modular level. Therefore, monovalent binding affinities of the individual SH3 domains to the individual PRM peptides were determined. This revealed one particular strong binding motif, PRM4, with dissociation constants of ~200 µM, 6 µM and 35 µM for SH3A, SH3B and SH3C, respectively. The promiscuous interaction further comprises four medium affine binding motifs (PRM1, PRM3, PRM5 and PRM6) with dissociation constants in the range of ~60 µM to 1 mM, and two weakly binding motifs (PRM2 and PRM*) with dissociation constants above 1 mM.Next, the question was addressed whether PRM4 or SH3B are main drivers for phase separation. Therefore, mutant constructs were designed. Weak (inactivated PRM4) and strong (3xPRM4) binding constructs of SLP65, and a strong binding construct of CIN85-3SH3 (3SH3B) were expressed. Pre-signaling clusters can be reconstituted in vitro with SLP65-and CIN85 protein constructs together with small unilamellar vesicles (SUVs).

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Role of Sam68 as an adaptor protein in inflammatory signaling

Gowd,

Kass,

Sarkar

et al. 2024

Cell. Mol. Life Sci.

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Sam68 is a ubiquitously expressed KH-domain containing RNA-binding protein highly studied for its involvement in regulating multiple steps of RNA metabolism. Sam68 also contains multiple protein–protein interaction regions such as proline-rich regions, tyrosine phosphorylation sites, and arginine methylation sites, all of which facilitate its participation as an adaptor protein in multiple signaling pathways, likely independent of its RNA-binding role. This review focuses on providing a comprehensive report on the adaptor roles of Sam68 in inflammatory signaling and inflammatory diseases. The insights presented here have the potential to open new avenues in inflammation research and justify targeting Sam68 to control aberrant inflammatory responses.

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Adaptor proteins: Flexible and dynamic modulators of immune cell signalling

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 16 publications

References 263 publications

Biochemical Analysis of Slam – a polarity protein during early Drosophila embryogenesis

Biochemical Analysis of Slam – a polarity protein during early Drosophila embryogenesis

Biophysical characterization and computational modeling of phase separation of immune adapter proteins

Role of Sam68 as an adaptor protein in inflammatory signaling

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