N-Terminal Palmitoylation of PSD-95 Regulates Association with Cell Membranes and Interaction with K+ Channel Kv1.4

Topinka, Jan; Bredt, David S.

doi:10.1016/s0896-6273(00)80440-7

Cited by 274 publications

(243 citation statements)

References 51 publications

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“…4E; extent of recovery 8 Ϯ 2% full vs. 10 Ϯ 3% partial). In contrast, when PSD-95-GFP was expressed in glia, where it is palmitoylated and targeted to the plasma membrane (34), photobleaching with the same protocol revealed a rapid biphasic recovery with a halfrecovery time of 1.7 sec ( Fig. 4E; extent of recovery 77 Ϯ 8%), consistent with our modeling results and D Ϸ 0.1 m 2 /sec (Fig.…”

Section: Resultssupporting

confidence: 85%

Structural plasticity with preserved topology in the postsynaptic protein network

Blanpied

Kerr

Ehlers

2008

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

119

104

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The size, shape, and molecular arrangement of the postsynaptic density (PSD) determine the function of excitatory synapses in the brain. Here, we directly measured the internal dynamics of scaffold proteins within single living PSDs, focusing on the principal scaffold protein PSD-95. We found that individual PSDs undergo rapid, continuous changes in morphology driven by the actin cytoskeleton and regulated by synaptic activity. This structural plasticity is accompanied by rapid fluctuations in internal scaffold density over submicron distances. Using targeted photobleaching and photoactivation of PSD subregions, we show that PSD-95 is nearly immobile within the PSD, and PSD subdomains can be maintained over long periods. We propose a flexible matrix model of the PSD based on stable molecular positioning of PSD-95 scaffolds.

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Section: Resultssupporting

confidence: 85%

Structural plasticity with preserved topology in the postsynaptic protein network

Blanpied

Kerr

Ehlers

2008

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

119

104

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“…This is in contrast to Drosophila DLG, which is localized to septate junctions through its second PDZ domain and a unique HOOK region found between the SH3 and GK domains (Thomas et al, 2000). The amino- terminus of other MAGUKs have also been found to act as subcellular localization signals; for example, the amino-terminus of PSD-95 is palmitoylated to allow its membrane association (Topinka and Bredt, 1998). Presumably by dedicating a unique localization domain independent of the other protein-protein interactions domains, MAGUKs can facilitate their own localization while maintaining the maximum number of valences for other binding partners.…”

Section: Discussionmentioning

confidence: 89%

DLG-1 Is a MAGUK Similar to SAP97 and Is Required for Adherens Junction Formation

Firestein¹,

Rongo

2001

MBoC

118

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Cellular junctions are critical for intercellular communication and for the assembly of cells into tissues. Cell junctions often consist of tight junctions, which form a permeability barrier and prevent the diffusion of lipids and proteins between cell compartments, and adherens junctions, which control the adhesion of cells and link cortical actin filaments to attachment sites on the plasma membrane. Proper tight junction formation and cell polarity require the function of membrane-associated guanylate kinases (MAGUKs) that contain the PDZ protein-protein interaction domain. In contrast, less is known about how adherens junctions are assembled. Here we describe how the PDZ-containing protein DLG-1 is required for the proper formation and function of adherens junctions in Caenorhabditis elegans. DLG-1 is a MAGUK protein that is most similar in sequence to mammalian SAP97, which is found at both synapses of the CNS, as well as at cell junctions of epithelia. DLG-1 is localized to adherens junctions, and DLG-1 localization is mediated by an amino-terminal domain shared with SAP97 but not found in other MAGUK family members. DLG-1 recruits other proteins and signaling molecules to adherens junctions, while embryos that lack DLG-1 fail to recruit the proteins AJM-1 and CPI-1 to adherens junctions. DLG-1 is required for the proper organization of the actin cytoskeleton and for the morphological elongation of embryos. In contrast to other proteins that have been observed to affect adherens junction assembly and function, DLG-1 is not required to maintain cell polarity. Our results suggest a new function for MAGUK proteins distinct from their role in cell polarity. INTRODUCTIONCell adhesion facilitates the assembly of individual cells into organized tissues, and several different cell adhesion mechanisms fulfill this role (Gumbiner, 1996). One of these adhesion mechanisms is the formation of the tight junction or zonula occludens, which functions to regulate the permeability of the cell layer and to polarize the cell surface into apical and basolateral compartments (Mitic and Anderson, 1998). Tight junctions (in vertebrates) and septate junctions (in invertebrates) maintain the separation between the apical and basolateral surfaces by hindering the diffusion of lipids and proteins (Powell, 1981;Gumbiner, 1987). In contrast to tight junctions, a second mechanism of cell adhesion is the adherens junction, which is responsible for maintaining adhesion between neighboring cells and is important for intercellular communication (Muller, 2000;Vasioukhin and Fuchs, 2001).While many proteins have important roles in assembling these junctions, mutations in these proteins result in large defects in cell polarity as well. For example, mutations in the Drosophila genes bazooka (baz), crumbs (crb), discs lost (dlt), scribble (scrib), lethal (1) discs large (dlg), and lethal giant larvae (lgl), and the Caenorhabditis elegans gene let-413 disrupt epithelial cell polarity and prevent the formation of cell junctions (Legouis et al., 20...

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“…S1). We also mutated the two palmitoylated cysteine residues at the N terminus to serines, as previously described (29), to make a palmitoylation-deficient version of the PSD95 FRET sensor (C3,5S-Ch-PSD95-V; Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Palmitoylation regulates glutamate receptor distributions in postsynaptic densities through control of PSD95 conformation and orientation

Jeyifous

Lin

Chen

et al. 2016

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

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Postsynaptic density protein 95 (PSD95) and synapse-associated protein 97 (SAP97) are homologous scaffold proteins with different N-terminal domains, possessing either a palmitoylation site (PSD95) or an L27 domain (SAP97). Here, we measured PSD95 and SAP97 conformation in vitro and in postsynaptic densities (PSDs) using FRET and EM, and examined how conformation regulated interactions with AMPA-type and NMDA-type glutamate receptors (AMPARs/NMDARs). Palmitoylation of PSD95 changed its conformation from a compact to an extended configuration. PSD95 associated with AMPARs (via transmembrane AMPAR regulatory protein subunits) or NMDARs [via glutamate ionotropic receptor NMDA-type subunit 2B (GluN2B) subunits] only in its palmitoylated and extended conformation. In contrast, in its extended conformation, SAP97 associates with NMDARs, but not with AMPARs. Within PSDs, PSD95 and SAP97 were largely in the extended conformation, but had different orientations. PSD95 oriented perpendicular to the PSD membrane, with its palmitoylated, N-terminal domain at the membrane. SAP97 oriented parallel to the PSD membrane, likely as a dimer through interactions of its N-terminal L27 domain. Changing PSD95 palmitoylation in PSDs altered PSD95 and AMPAR levels but did not affect NMDAR levels. These results indicate that in PSDs, PSD95 palmitoylation, conformation, and its interactions are dynamic when associated with AMPARs and more stable when associated with NMDARs. Altogether, our results are consistent with differential regulation of PSD95 palmitoylation in PSDs resulting from the clustering of palmitoylating and depalmitoylating enzymes into AMPAR nanodomains segregated away from NMDAR nanodomains.P ostsynaptic densities (PSDs) at glutamatergic synapses organize and hold NMDA receptors (NMDARs), AMPA receptors (AMPARs), and other signaling molecules in place, apposed to sites of neurotransmitter release. Just below the PSD plasma membrane lies a latticework of vertical and parallel filaments that provides a structural scaffold to stabilize synaptic signaling molecules within PSDs (1, 2). Postsynaptic density protein 95 (PSD95) and synapse-associated protein 97 (SAP97) are members of a family of membrane-associated guanylate kinases (MAGUKs) (3). PSD95 is the most abundant scaffold protein in adult synapses, with ∼300 PSD95 molecules (2.3% of the mass of the PSD) in the average PSD, and is part of the lattice forming the core of the PSD (4). SAP97 is also a component of the PSD lattice. Estimates of its PSD copy numbers range from 90 SAP97 molecules per average PSD [0.9% of the mass of the PSD (4)] to lower values (5). As MAGUKs, PSD95 and SAP97 share a series of highly homologous protein-interacting domains but diverge at their N-terminal domains, which affects their trafficking into and out of the PSD, as well as interactions with AMPARs and NMDARs (3, 6, 7). The SAP97β-isoform, like almost all SAP97 molecules, contains an N-terminal L27 domain that interacts with other L27 domaincontaining proteins, particularly with a differ...

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N-Terminal Palmitoylation of PSD-95 Regulates Association with Cell Membranes and Interaction with K+ Channel Kv1.4

Cited by 274 publications

References 51 publications

Structural plasticity with preserved topology in the postsynaptic protein network

Structural plasticity with preserved topology in the postsynaptic protein network

DLG-1 Is a MAGUK Similar to SAP97 and Is Required for Adherens Junction Formation

Palmitoylation regulates glutamate receptor distributions in postsynaptic densities through control of PSD95 conformation and orientation

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