Intramolecular domain dynamics regulate synaptic MAGUK protein interactions

Rademacher, Nils; Kuropka, Benno; Kunde, Stella-Amrei; Wahl, Markus C.; Freund, Christian; Shoichet, Sarah A.

doi:10.7554/elife.41299

Cited by 38 publications

(25 citation statements)

References 58 publications

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“…Surprisingly, we observe that not only α 3 affects the allosteric network in PDZ3, but there is a substantial difference when the domain is studied in isolation as compared to when it is part of the PSG supramodule. This finding is in line with previous studies indicating that the allostery is mediated through interdomain communication by protein-protein interactions (15,18).…”

Section: Discussionsupporting

confidence: 93%

“…6 A and B). In accordance with previous findings (18,38) we propose that the allosteric network propagates to new sites in the context of the supramodule. Zhang et al, showed that the PSG from PSD-95 changes from compact to extended conformation upon CRIPT binding, which disturbs PDZ3:SH3 Interdomain interactions at the β 1 β 2 loop, β 2 sheet, and α 2 and α 3 helix in PDZ3 (38).…”

Section: Discussionsupporting

confidence: 92%

“…Zhang et al, showed that the PSG from PSD-95 changes from compact to extended conformation upon CRIPT binding, which disturbs PDZ3:SH3 Interdomain interactions at the β 1 β 2 loop, β 2 sheet, and α 2 and α 3 helix in PDZ3 (38). The interdomain dynamics of PDZ3:SH3 indicates that the PSG supramodule is flexible and changes interdomain conformation in response to ligand binding (38), which is supported by our results and other recent findings showing that intramolecular domain dynamics regulate the binding properties and conformations of the PSG supramodule (18). However, the interactions mediated by the β 1 β 2 and β 2 β 3 loops could be a general feature for PDZ supertertiary organization as reported for the PDZ1-2 tandem (41).…”

Section: Discussionsupporting

confidence: 89%

“…S1). The potential role of the adjacent domains in the supramodule is particularly relevant since binding of protein ligands to the SH3-GK tandem is modulated by binding of cysteine-rich interactor of PDZ3 (CRIPT) to PDZ3 (18).…”

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confidence: 99%

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Supertertiary protein structure affects an allosteric network

Laursen

Kliche

Gianni

et al. 2020

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

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The notion that protein function is allosterically regulated by structural or dynamic changes in proteins has been extensively investigated in several protein domains in isolation. In particular, PDZ domains have represented a paradigm for these studies, despite providing conflicting results. Furthermore, it is still unknown how the association between protein domains in supramodules, consitituting so-called supertertiary structures, affects allosteric networks. Here, we experimentally mapped the allosteric network in a PDZ:ligand complex, both in isolation and in the context of a supramodular structure, and show that allosteric networks in a PDZ domain are highly dependent on the supertertiary structure in which they are present. This striking sensitivity of allosteric networks to the presence of adjacent protein domains is likely a common property of supertertiary structures in proteins. Our findings have general implications for prediction of allosteric networks from primary and tertiary structures and for quantitative descriptions of allostery.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

See 2 more Smart Citations

Supertertiary protein structure affects an allosteric network

Laursen

Kliche

Gianni

et al. 2020

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

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“…Moreover, the rate constants differ so that one conformer binds CRIPT faster than the other one, reflecting changes around the binding groove associated with the conformational transition. Previous work demonstrated conformational transitions within the PSG using structural approaches (8,9), and more recently, functional oligomerization has been shown to be dependent on the PSG supramodule (17,(21)(22)(23). The binding kinetics observed in this study could be related to these phenomena.…”

supporting

confidence: 55%

Functional interplay between protein domains in a supramodular structure involving the postsynaptic density protein PSD-95

Laursen

Karlsson

Gianni

et al. 2020

Journal of Biological Chemistry

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Cell scaffolding and signaling are governed by protein–protein interactions. Although a particular interaction is often defined by two specific domains binding to each other, this interaction often occurs in the context of other domains in multidomain proteins. How such adjacent domains form supertertiary structures and modulate protein–protein interactions has only recently been addressed and is incompletely understood. The postsynaptic density protein PSD-95 contains a three-domain supramodule, denoted PSG, which consists of PDZ, Src homology 3 (SH3), and guanylate kinase-like domains. The PDZ domain binds to the C terminus of its proposed natural ligand, CXXC repeat–containing interactor of PDZ3 domain (CRIPT), and results from previous experiments using only the isolated PDZ domain are consistent with the simplest scenario for a protein–protein interaction; namely, a two-state mechanism. Here we analyzed the binding kinetics of the PSG supramodule with CRIPT. We show that PSG binds CRIPT via a more complex mechanism involving two conformational states interconverting on the second timescale. Both conformational states bound a CRIPT peptide with similar affinities but with different rates, and the distribution of the two conformational states was slightly shifted upon CRIPT binding. Our results are consistent with recent structural findings of conformational changes in PSD-95 and demonstrate how conformational transitions in supertertiary structures can shape the ligand-binding energy landscape and modulate protein–protein interactions.

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Zinc‐chelating postsynaptic density‐95 N‐terminus impairs its palmitoyl modification

et al. 2021

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Chemical synaptic transmission represents the most sophisticated dynamic process and is highly regulated with optimized neurotransmitter balance. Imbalanced transmitters can lead to transmission impairments, for example, intracellular zinc accumulation is a hallmark of degenerating neurons. However, the underlying mechanisms remain elusive. Postsynaptic density protein‐95 (PSD‐95) is a primary postsynaptic membrane‐associated protein and the major scaffolding component in the excitatory postsynaptic densities, which performs substantial functions in synaptic development and maturation. Its membrane association induced by palmitoylation contributes largely to its regulatory functions at postsynaptic sites. Unlike other structural domains in PSD‐95, the N‐terminal region (PSD‐95NT) is flexible and interacts with various targets, which modulates its palmitoylation of two cysteines (C3/C5) and glutamate receptor distributions in postsynaptic densities. PSD‐95NT contains a putative zinc‐binding motif (C2H2) with undiscovered functions. This study is the first effort to investigate the interaction between Zn2+ and PSD‐95NT. The NMR titration of 15N‐labeled PSD‐95NT by ZnCl2 was performed and demonstrated Zn2+ binds to PSD‐95NT with a binding affinity (Kd) in the micromolar range. The zinc binding was confirmed by fluorescence and mutagenesis assays, indicating two cysteines and two histidines (H24, H28) are critical residues for the binding. These results suggested the concentration‐dependent zinc binding is likely to influence PSD‐95 palmitoylation since the binding site overlaps the palmitoylation sites, which was verified by the mimic PSD‐95 palmitoyl modification and intact cell palmitoylation assays. This study reveals zinc as a novel modulator for PSD‐95 postsynaptic membrane association by chelating its N‐terminal region, indicative of its importance in postsynaptic signaling.

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Intramolecular domain dynamics regulate synaptic MAGUK protein interactions

Cited by 38 publications

References 58 publications

Supertertiary protein structure affects an allosteric network

Supertertiary protein structure affects an allosteric network

Functional interplay between protein domains in a supramodular structure involving the postsynaptic density protein PSD-95

Zinc‐chelating postsynaptic density‐95 N‐terminus impairs its palmitoyl modification

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