Ligand‐dependent intra‐ and interdomain motions in the PDZ12 tandem regulate binding interfaces in postsynaptic density protein‐95

Kovács, Bertalan; Zajácz-Epresi, Nóra; Gáspári, Zoltán

doi:10.1002/1873-3468.13626

Cited by 9 publications

(7 citation statements)

References 52 publications

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“…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). Taken together, the data show the importance of three structural elements for inter-and intradomain structural conformation and communication: the α 3 helix and the β 1 β 2 and β 2 β 3 loops.…”

Section: Discussionsupporting

confidence: 90%

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: 90%

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 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 b1b2 and b2b3 loops could be a general feature for PDZ supertertiary organization as reported for the PDZ1-2 tandem (41). Taken together, the data show the importance of three structural elements for inter-and intradomain structural conformation and communication: the a3 helix, and the b1b2 and b2b3 loops.…”

Section: Supertertiary Structure Affects the Allosteric Network In Pdz3supporting

confidence: 90%

Supertertiary protein structure affects an allosteric network

Laursen

Kliche

Gianni

et al. 2020

Preprint

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Corresponding authors: Stefano.Gianni@uniroma1.it; Per.Jemth@imbim.uu.seThe 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 structure, 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 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 structure and for quantitative descriptions of allostery. Abstract IntroductionAllosteric regulation is an essential function of many proteins, well established in multimeric proteins with well-defined conformational changes. From a biological perspective, such allostery plays important roles, for example in regulation of enzyme activity and binding of oxygen to hemoglobin, which was the basis for models such as MWC (1) and KNF (2). More recently the concept has been extended to monomeric proteins (3) and intrinsically disordered proteins (4, 5). Here, allostery is a process, where a signal propagates from one site to a physically distinct site, although the exact mechanism is elusive (6). Thus, as experimental approaches have developed the definition of the allosteric mechanism has evolved too and it is now spanning from the classical structure based allostery to the ensemble nature of allostery, and provides the framework for capturing allostery from rigid and structured proteins to dynamic and disordered proteins (7).PDZ3 from PSD-95 has been extensively used as a model system for allostery in a single protein domain. Originally, it was used as a benchmark of a statistical method to predict allostery from co-variation of mutations (8) and has since then been subject to study by numerous methods (9). PDZ domains are small protein domains, around 100 amino acid residues, with a specific fold that contains 5-6 b strands and 2-3 a-helices ( Figure 1C). The PDZ domain family is one of the most abundant protein-protein interaction domains in humans and it is often found in scaffolding or signalling proteins. PDZ domains bind to short interaction motifs (3-6 residues), usually at the C-terminus of ligand proteins. Looking at PDZ3 as a system to understand principles that underlie allosteric regulation reveals the complexity of the phenomenon. The first allosteric network in PDZ3 was determined by statistical coupling analysis and depicted a network that propagates f...

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“…5C). This result, which supports the idea that these three proteins indeed cooperate functionally, is in line with studies on macromolecular complex formation dictated by other MAGUKs: complex formation induced by ligand binding to PSD-95 PDZ domains has been demonstrated in both in vitro and cellular contexts [44][45][46][47] .…”

Section: Discussionsupporting

confidence: 89%

JNK activity modulates postsynaptic scaffold protein SAP102 and kainate receptor dynamics in dendritic spines

Kunde¹,

Schmerl²,

Ahmadyar³

et al. 2021

Preprint

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We show here that the dynamics of the synaptic scaffold molecule SAP102 are negatively regulated by JNK inhibition, that SAP102 is a direct phosphorylation target of JNK3, and that SAP102 regulation by JNK is restricted to neurons that harbour mature synapses. We further demonstrate that SAP102 and JNK3 cooperate in the regulated trafficking of kainate receptors to the cell membrane. Specifically, we observe that SAP102, JNK3, and the kainate receptor subunit GluK2 exhibit overlapping expression at synaptic sites, and that modulating JNK activity influences the surface expression of the kainate receptor subunit GluK2 in a neuronal context. We also show that SAP102 participates in this process in a JNK-dependent fashion. In summary, our data support a model in which JNK-mediated regulation of SAP102 influences the dynamic trafficking of kainate receptors to postsynaptic sites, and thus shed light on common pathophysiological mechanisms underlying the cognitive developmental defects associated with diverse mutations.

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Ligand‐dependent intra‐ and interdomain motions in the PDZ12 tandem regulate binding interfaces in postsynaptic density protein‐95

Cited by 9 publications

References 52 publications

Supertertiary protein structure affects an allosteric network

Supertertiary protein structure affects an allosteric network

Supertertiary protein structure affects an allosteric network

JNK activity modulates postsynaptic scaffold protein SAP102 and kainate receptor dynamics in dendritic spines

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