Interaction of the Postsynaptic Density-95/Guanylate Kinase Domain-Associated Protein Complex with a Light Chain of Myosin-V and Dynein

Naisbitt, Scott; Valtschanoff, Juli G.; Allison, Daniel W.; Sala, Carlo; Kim, Eunjoon; Craig, Ann Marie; Weinberg, Richard J.; Sheng, Morgan

doi:10.1523/jneurosci.20-12-04524.2000

Cited by 255 publications

(231 citation statements)

References 57 publications

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“…It has recently been suggested that electrical activity controls the size and number of spines 21,22,[39][40][41][42] , and that the expression of glutamate receptors is tightly regulated by abundant cytoskeletal structures present in spines [3][4][5] . One can therefore surmise that spine structures are a key determinant of synaptic efficacy via control of the distribution of the AMPA receptors 9,10,43 .…”

Section: Discussionmentioning

confidence: 99%

“…Nonstationary fluctuation analysis was performed based on the following equation (4) Here, σb 2 stands for base line variance; i, single channel current; and N, the number of AMPA receptors 37 . The 2pEPSCs were filtered at 2 kHz and sampled at 10 kHz.…”

Section: Analysis Of 2pepscsmentioning

confidence: 99%

“…Substantial biochemical evidence indicates that glutamate receptors in postsynaptic densities (PSDs) are regulated by various protein machineries that link the receptors to the cytoskeleton 3,4,5 and that control the insertion [6][7][8][9][10] and phosphorylation of the receptors 11,12 . Individual dendritic spines have been thought to act as functional compartments of glutamate receptor expression, given that they are physically and thus metabolically separated from the body of the dendrite by the narrow spine neck [13][14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

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Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons

et al. 2001

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Dendritic spines serve as preferential sites of excitatory synaptic connections and are pleomorphic. To address the structure-function relationship of the dendritic spines, we used two-photon uncaging of glutamate to allow mapping of functional glutamate receptors at the level of the single synapse. Our analyses of the spines of CA1 pyramidal neurons reveal that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors are abundant (up to 150/ spine) in mushroom spines but sparsely distributed in thin spines and filopodia. The latter may be serving as the structural substrates of the silent synapses that have been proposed to play roles in development and plasticity of synaptic transmission. Our data indicate that distribution of functional AMPA receptors is tightly correlated with spine geometry and that receptor activity is independently regulated at the level of single spines.Most excitatory synaptic transmission in the mammalian central nervous system relies on glutamate as a neurotransmitter, and postsynaptic glutamate receptors are central in both the acquisition and maintenance of memory 1, 2 . Substantial biochemical evidence indicates that glutamate receptors in postsynaptic densities (PSDs) are regulated by various protein machineries that link the receptors to the cytoskeleton 3,4,5 and that control the insertion [6][7][8][9][10] and phosphorylation of the receptors 11,12 . Individual dendritic spines have been thought to act as functional compartments of glutamate receptor expression, given that they are physically and thus metabolically separated from the body of the dendrite by the narrow spine neck [13][14][15][16] . Indeed, the Hebbian principle of learning as well as most theories of neuronal networks assume that the strength of synaptic connections is subject to independent control 17 . Moreover, spine geometry has been proposed to be a key determinant of synaptic function and memory in the brain 13, 14, 18-22 . Correspondence to: Haruo Kasai. These various hypotheses have not been tested experimentally, however, because it is not possible to systematically investigate postsynaptic glutamate sensitivities at the level of the individual spine by classical electrophysiological approaches 16,23 . Also, the number of functional AMPA-sensitive glutamate receptors in individual spines has not been estimated directly. Two-photon excitation of caged-glutamate compounds may overcome these difficulties 24 as a result of the inherent three-dimensional resolution of neurotransmitter application associated with this technique. However, caged-glutamate compounds with a cross-section for two-photon absorption, a rate of photolysis, and a stability in aqueous solution sufficient for such studies have not previously been described [25][26][27] . NIH Public AccessWe developed a caged-glutamate compound and microscopic system for two-photon excitation that allowed systematic investigation of functional glutamate receptors at the level of the individual synapse. Our experiment...

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of 2pepscsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons

et al. 2001

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“…The splice variant ACE however is exclusively detected in human epidermal melanocytes (unpublished results). In rat brain, the specific myosin Va variant ABCE appears together with dynein and their common LC DLC8 in a coimmunoprecipitable complex with a postsynaptic scaffold protein that organizes a cytoskeletal-signaling complex at the postsynaptic membrane (63). Creating different splice variants of a particular gene are nature's tool to regulate, e.g.…”

Section: Alternative Splicing: Making the Motor Complexes Even More Cmentioning

confidence: 99%

The Dilute Locus and Griscelli Syndrome: Gateways Towards a Better Understanding of Melanosome Transport

Westbroek

Lambert

Naeyaert

2001

Pigment Cell Research

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would present a major breakthrough in the possibilities to In this review an overview of recent advances in the understanding of melanosome movement within epidermal influence pigmentation and related disorders, of great concern melanocytes is given. Exploration of the molecular events to some patients. Moreover, melanosome transport offers a good model to study mammalian organelle trafficking and its involved in and determining the process of melanosome transkey players in general. port, as an essential part of human pigmentation, could lead to the identification of agents that augment, or down-regulate the Key words: Actin, Melanocyte, Motor proteins, Tubulin transfer of melanosomes to surrounding keratinocytes. This in melanosome transport has stagnated somewhat, and the focus was aimed at new molecular families involved in vesicle trafficking. Starting from an overview of the knowledge obtained with relation to molecular motors, the newly discovered involvement and co-operation of other molecules will be summarized in this review. Finally, this collection of findings is depicted graphically in Fig. 1.

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“…Detailed kinetic and thermodynamic characterization of this interaction using monoand dimeric myo5a fragments revealed that the dissociation constant is somewhat weaker than that of the canonical motifs(~1-5 M for a monomeric peptide) andbivalency of the ligand leads to pronounced avidity (18). hypothesized that DYNLL may provide direct physical linkage between the motor and the cargos (26,28,29). However, as the majority of the binding partners (including the motors) are dimeric, and therefore they are bivalent ligands of LC8 and the formation of highly stable dimer-to-dimer complexes is preferred (18).…”

mentioning

confidence: 99%

DYNLL2 Dynein Light Chain Binds to an Extended Linear Motif of Myosin 5a Tail That Has Structural Plasticity

Bodor¹,

Radnai²,

Hetényi

et al. 2014

Biochemistry

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LC8 dynein light chains (DYNLL) are conserved homodimeric eukaryotic hub proteins that participate in diverse cellular processes. Among the binding partners of DYNLL2, myosin 5a (myo5a) is a motor protein involved in cargo transport. Here we provide a profound characterization of the DYNLL2 binding motif of myo5a in free and DYNLL2 bound form by using NMR spectroscopy, Xray crystallography and molecular dynamics simulations. In the free form the DYNLL2 binding region, located in an intrinsically disordered domain of the myo5a tail, has a nascent helical character. The motif becomes structured and folds into a β-strand upon binding to DYNLL2. Despite all differences of the myo5a sequence from the consensus binding motif, it accommodates into the same DYNLL2 binding groove as all other partners do. Interestingly, while the core motif shows similar interaction pattern in the binding groove as seen inother complexes, the flanking residues make several additional contacts, thereby lengthening the binding motif. The N-terminal extension folds back and partially blocks the free edge of the β-sheet formed by the binding motif itself. The C-terminal extension contacts the dimer interface and interacts with symmetry related residues of the second myo5a peptide. The involvement of flanking residues of the core binding site of myo5a could modify the quaternary structure of the full-length myo5a and affect its biological functions. The presented structural data widen our understanding of the diverse partner recognition of DYNLL proteins and provide an example of a Janus-faced linear motif. 4The LC8 dynein light chains were originally described as the smallest subunit of the microtubuleassociated cytoplasmic dynein motor complex.They show a highly conserved amino acid sequence throughout evolution and they were later shown to bind to more than 70 other proteins involved in various biological processes, therefore they are now considered hub proteins (1, 2).Vertebrates contain two closely related LC8 paralogs, DYNLL1 and DYNLL2 with partially overlapping functions(1). Under physiological conditions LC8proteins arestable homodimers (3).Atomic resolution structureswere determined both for the apo and ligand-bound form using X-ray crystallographyand NMR spectroscopy (4-6). Five β-strands make up two core β-sheets; one sideof each sheet is flanked by two α-helices, and the otherside forms the dimer interface. The β3-strand of one subunit pairs to theβ2"-strandof the other subunitin an antiparallel mode; and the dimer is stabilized by interface contacts through hydrophobic interactions and side chain H-bonds. Two equivalent grooves are formed and they represent the target binding pockets of the dimer. The primary transcript of the human MYO5A geneis processed by alternative splicing (13). Three exons 5 within the tail domain (B, D, and F) are expressed in a cell type-specific manner; the predominant melanocyte-and brain-specific isoforms contains exons D, F, and exon B, respectively (13). The exon pattern of myo5a tail lik...

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Interaction of the Postsynaptic Density-95/Guanylate Kinase Domain-Associated Protein Complex with a Light Chain of Myosin-V and Dynein

Cited by 255 publications

References 57 publications

Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons

Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons

The Dilute Locus and Griscelli Syndrome: Gateways Towards a Better Understanding of Melanosome Transport

DYNLL2 Dynein Light Chain Binds to an Extended Linear Motif of Myosin 5a Tail That Has Structural Plasticity

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