scholarly journals Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments

2020 ◽  
Author(s):  
Verena Henrichs ◽  
Lenka Grycova ◽  
Cyril Barinka ◽  
Zuzana Nahacka ◽  
Jiri Neuzil ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Intracellular Trafficking ◽  
Adaptor Protein ◽  
Direct Interaction ◽  
Run Length ◽  
Cell Lysate ◽  
Mitochondrial Trafficking ◽  
Protein Crowding ◽  
Crowded Environments

SummaryIntracellular trafficking of organelles, driven by kinesin-1 stepping along microtubules, underpins essential processes including neuronal activity. In absence of other proteins on the microtubule surface, kinesin-1 performs micron-long runs. Under protein crowding conditions, however, kinesin-1 motility is drastically impeded. It is thus unclear how kinesin-1 acts as an efficient transporter in crowded intracellular environments. Here, we demonstrate that TRAK1 (Milton), an adaptor protein essential for mitochondrial trafficking, activates kinesin-1 and increases its robustness of stepping in protein crowding conditions. Interaction with TRAK1 i) facilitated kinesin-1 navigation around obstacles, ii) increased the probability of kinesin-1 passing through cohesive envelopes of tau and iii) increased the run length of kinesin-1 in cell lysate. We explain the enhanced motility by the observed direct interaction of TRAK1 with microtubules, providing an additional anchor for the kinesin-1-TRAK1 complex. We propose adaptor-mediated tethering as a mechanism regulating kinesin-1 motility in various cellular environments.

scholarly journals Adaptor protein APPL1 links neuronal activity to chromatin remodeling in cultured hippocampal neurons

2020 ◽  
Author(s):  
Yu Wu ◽  
Xinyou Lv ◽  
Haiting Wang ◽  
Kai Qian ◽  
Jinjun Ding ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Late Phase ◽  
Adaptor Protein ◽  
Long Term Potentiation ◽  
Nuclear Accumulation ◽  
Transcriptional Responses ◽  
Axon Terminals ◽  
Term Potentiation

Abstract Local signaling events at synapses or axon terminals are communicated to the nucleus to elicit transcriptional responses, and thereby translate information about the external environment into internal neuronal representations. This retrograde signaling is critical to dendritic growth, synapse development, and neuronal plasticity. Here, we demonstrate that neuronal activity induces retrograde translocation and nuclear accumulation of endosomal adaptor APPL1. Disrupting the interaction of APPL1 with Importin α1 abolishes nuclear accumulation of APPL1, which in turn decreases the levels of histone acetylation. We further demonstrate that retrograde translocation of APPL1 is required for the regulation of gene transcription and then maintenance of hippocampal late-phase long-term potentiation. Thus, these results illustrate an APPL1-mediated pathway that contributes to the modulation of synaptic plasticity via coupling neuronal activity with chromatin remodeling.

scholarly journals Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent

2006 ◽  
Vol 173 (4) ◽  
pp. 545-557 ◽  
Author(s):  
Elizabeth E. Glater ◽  
Laura J. Megeath ◽  
R. Steven Stowers ◽  
Thomas L. Schwarz
Keyword(s):  
Heavy Chain ◽  
Light Chain ◽  
Adaptor Protein ◽  
Direct Interaction ◽  
Anterograde Transport ◽  
Kinesin Light Chain ◽  
Energy Demands ◽  
Kinesin Heavy Chain ◽  
Conventional Kinesin ◽  
Dependent Transport

Mitochondria are distributed within cells to match local energy demands. We report that the microtubule-dependent transport of mitochondria depends on the ability of milton to act as an adaptor protein that can recruit the heavy chain of conventional kinesin-1 (kinesin heavy chain [KHC]) to mitochondria. Biochemical and genetic evidence demonstrate that kinesin recruitment and mitochondrial transport are independent of kinesin light chain (KLC); KLC antagonizes milton's association with KHC and is absent from milton–KHC complexes, and mitochondria are present in klc −/− photoreceptor axons. The recruitment of KHC to mitochondria is, in part, determined by the NH2 terminus–splicing variant of milton. A direct interaction occurs between milton and miro, which is a mitochondrial Rho-like GTPase, and this interaction can influence the recruitment of milton to mitochondria. Thus, milton and miro are likely to form an essential protein complex that links KHC to mitochondria for light chain–independent, anterograde transport of mitochondria.

scholarly journals A direct interaction between the adaptor protein Cbl-b and the kinase Zap-70 induces a positive signal in T cells

1999 ◽  
Vol 9 (4) ◽  
pp. 203-210 ◽  
Author(s):  
Zhihong Zhang ◽  
Chris Elly ◽  
Ling Qiu ◽  
Amnon Altman ◽  
Yun-Cai Liu
Keyword(s):  
T Cells ◽  
Adaptor Protein ◽  
Direct Interaction ◽  
Positive Signal

scholarly journals Realistic modeling of ephaptic fields in the human brain

2019 ◽  
Author(s):  
Giulio Ruffini ◽  
Ricardo Salvador ◽  
Ehsan Tadayon ◽  
Roser Sanchez-Todo ◽  
Alvaro Pascual-Leone ◽  
...  
Keyword(s):  
Human Brain ◽  
Electric Fields ◽  
Neuronal Activity ◽  
Direct Interaction ◽  
Pyramidal Cells ◽  
Brain Structures ◽  
Relative Orientation ◽  
Transcranial Brain Stimulation ◽  
Potential Perturbation ◽  
Human Function

AbstractSeveral decades of research suggest that weak electric fields may influence neural processing, including those induced by neuronal activity and recently proposed as substrate for a potential new cellular communication system, i.e., ephaptic transmission. Here we aim to map ephaptic activity in the human brain and explore its trajectory during aging by characterizing the macroscopic electric field generated by cortical dipoles using realistic finite element modeling. We find that modeled endogenous field magnitudes are comparable to those in measurements of weak but functionally relevant endogenous fields and to those generated by noninvasive transcranial brain stimulation, therefore possibly able to modulate neuronal activity. Then, to evaluate the role of self-generated ephaptic fields in the human cortex, we adapt an interaction approximation that considers the relative orientation of neuron and field to derive the membrane potential perturbation in pyramidal cells. Building on this, we define a simplified metric (EMOD1) that weights dipole coupling as a function of distance and relative orientation between emitter and receiver and evaluate it in a sample of 401 realistic human brain models from subjects aged 16-83. Results reveal that ephaptic modulation follows gyrification patterns in the human brain, and significantly decreases with age, with higher involvement of sensorimotor regions and medial brain structures. By providing the means for fast and direct interaction between neurons, ephaptic modulation likely contributes to the complexity of human function for cognition and behavior, and its modification across the lifespan and in response to pathology.

scholarly journals Activity-Regulated Cytoskeleton-Associated Protein Controls AMPAR Endocytosis through a Direct Interaction with Clathrin-Adaptor Protein 2

eNeuro ◽  
2016 ◽  
Vol 3 (3) ◽  
pp. ENEURO.0144-15.2016 ◽  
Author(s):  
Luis L. P. DaSilva ◽  
Mark J. Wall ◽  
Luciana P. de Almeida ◽  
Sandrine C. Wauters ◽  
Yunan C. Januário ◽  
...  
Keyword(s):  
Adaptor Protein ◽  
Direct Interaction ◽  
Clathrin Adaptor

scholarly journals Acentrosomal spindle assembly and stability in C. elegans oocytes requires a kinesin-12 non-motor microtubule interaction domain

2021 ◽  
Author(s):  
Ian Daniel Wolff ◽  
Jeremy Alden Hollis ◽  
Sarah Marie Wignall
Keyword(s):  
Adaptor Protein ◽  
Direct Interaction ◽  
Spindle Assembly ◽  
Meiotic Spindle ◽  
Interaction Domain ◽  
Microtubule Binding ◽  
C Elegans ◽  
Insight Into

During the meiotic divisions in oocytes, microtubules are sorted and organized by motor proteins to generate a bipolar spindle in the absence of centrosomes. In most organisms, kinesin-5 family members crosslink and slide microtubules to generate outward force that promotes acentrosomal spindle bipolarity. However, the mechanistic basis for how other kinesin families act on acentrosomal spindles has not been explored. We investigated this question in C. elegans oocytes, where kinesin-5 is not required to generate outward force. Instead, the kinesin-12 family motor KLP-18 performs this function. KLP-18 acts with adaptor protein MESP-1 (meiotic spindle 1) to sort microtubule minus ends to the periphery of a microtubule array, where they coalesce into spindle poles. If either of these proteins is depleted, outward sorting of microtubules is lost and minus ends converge to form a monoaster. Here we use a combination of in vitro biochemical assays and in vivo mutant analysis to provide insight into the mechanism by which these proteins collaborate to promote acentrosomal spindle assembly. We identify a microtubule binding site on the C-terminal stalk of KLP-18 and demonstrate that a direct interaction between the KLP-18 stalk and MESP-1 activates non-motor microtubule binding. We also provide evidence that this C-terminal domain is required for KLP-18 activity during spindle assembly and show that KLP-18 is continuously required to maintain spindle bipolarity. This study thus provides new insight into the construction and maintenance of the oocyte acentrosomal spindle as well as into kinesin-12 mechanism and regulation.

scholarly journals In Vitro Inhibitory Mechanism Effect of TRAIP on the Function of TRAF2 Revealed by Characterization of Interaction Domains

2018 ◽  
Vol 19 (8) ◽  
pp. 2457 ◽  
Author(s):  
Eijaz Bhat ◽  
Chang Kim ◽  
Sunghwan Kim ◽  
Hyun Park
Keyword(s):  
Coiled Coil ◽  
Adaptor Protein ◽  
Direct Interaction ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Inhibitory Mechanism ◽  
Concentration Dependent Manner ◽  
Critical Function

TRAF-interacting protein (TRAIP), a negative regulator of TNF-induced-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, inhibits adaptor protein TRAF2 by direct interaction and is critical in apoptosis, cell proliferation, antiviral response, and embryonic development. Although the critical function of TRAIP in NF-κB signaling is well-known, the molecular inhibitory mechanism of TRAIP remains unclear. We found that the TRAIP coiled-coil domain altered its stoichiometry between dimer and trimer in a concentration-dependent manner. Additionally, the TRAIP RING domain induced even higher-ordered assembly, which was necessary for interacting with the TRAF-N domain of TRAF2 but not TRAF1. Characterization of the TRAF-N domains of TRAF1 and TRAF2, the tentative TRAIP-binding region of TRAFs, suggested the molecular basis of the inhibitory effect of TRAIP on TRAF2 in NF-κB signaling.

scholarly journals The adaptor protein AP-4 as a component of the clathrin coat machinery: a morphological study

2005 ◽  
Vol 385 (2) ◽  
pp. 503-510 ◽  
Author(s):  
Nicolas BAROIS ◽  
Oddmund BAKKE
Keyword(s):  
Golgi Complex ◽  
Intracellular Trafficking ◽  
Intracellular Localization ◽  
Adaptor Protein ◽  
Immunogold Labelling ◽  
Endocytic Pathway ◽  
Transport Vesicles ◽  
Cargo Proteins ◽  
The Difference ◽  
First Time

The four members of the AP (adaptor protein) family are heterotetrameric cytosolic complexes that are involved in the intracellular trafficking of cargo proteins between different organelles. They interact with motifs present in the cytoplasmic tails of their specific cargo proteins at different intracellular locations. While AP-1, AP-2 and AP-3 have been investigated extensively, very few studies have focused on the fourth member, AP-4. In the present study, we report on the intracellular localization of AP-4 in the MDCK (Madin–Darby canine kidney) and MelJuSo cell lines after immunogold labelling of ultrathin cryosections. We find that AP-4 is localized mainly in the Golgi complex, as well as on endosomes and transport vesicles. Interestingly, we show for the first time that AP-4 is localized with the clathrin coat machinery in the Golgi complex and in the endocytic pathway. Furthermore, we find that AP-4 is localized with the CI-MPR (cation-independent mannose 6-phosphate receptor), but not with the transferrin receptor, LAMP-2 (lysosomal-associated membrane protein-2) or invariant chain. The difference in morphology between CI-MPR/AP-4-positive vesicles and CI-MPR/AP-1-positive vesicles raises the possibility that AP-4 acts at a location different from that of AP-1 in the intracellular trafficking pathway of CI-MPR.

scholarly journals Circovirus Transport Proceeds via Direct Interaction of the Cytoplasmic Dynein IC1 Subunit with the Viral Capsid Protein

2014 ◽  
Vol 89 (5) ◽  
pp. 2777-2791 ◽  
Author(s):  
Jingjing Cao ◽  
Cui Lin ◽  
Huijuan Wang ◽  
Lun Wang ◽  
Niu Zhou ◽  
...  
Keyword(s):  
Intracellular Trafficking ◽  
Molecular Mechanisms ◽  
Molecular Motor ◽  
Direct Interaction ◽  
Retrograde Transport ◽  
Cytoplasmic Dynein ◽  
Virus Transport ◽  
Antiviral Therapies ◽  
Early Endosomes ◽  
Replication Sites

ABSTRACTMicrotubule transport of circovirus from the periphery of the cell to the nucleus is essential for viral replication in early infection. How the microtubule is recruited to the viral cargo remains unclear. In this study, we observed that circovirus trafficking is dependent on microtubule polymerization and that incoming circovirus particles colocalize with cytoplasmic dynein and endosomes. However, circovirus binding to dynein was independent of the presence of microtubular α-tubulin and translocation of cytoplasmic dynein into the nucleus. The circovirus capsid (Cap) subunit enhanced microtubular acetylation and directly interacted with intermediate chain 1 (IC1) of dynein. N-terminal residues 42 to 100 of the Cap viral protein were required for efficient binding to the dynein IC1 subunit and for retrograde transport. Knockdown of IC1 decreased virus transport and replication. These results demonstrate that Cap is a direct ligand of the cytoplasmic dynein IC1 subunit and an inducer of microtubule α-tubulin acetylation. Furthermore, Cap recruits the host dynein/microtubule machinery to facilitate transport toward the nucleus by an endosomal mechanism distinct from that used for physiological dynein cargo.IMPORTANCEIncoming viral particles hijack the intracellular trafficking machinery of the host in order to migrate from the cell surface to the replication sites. Better knowledge of the interaction between viruses and virus proteins and the intracellular trafficking machinery may provide new targets for antiviral therapies. Currently, little is known about the molecular mechanisms of circovirus transport. Here, we report that circovirus particles enter early endosomes and utilize the microtubule-associated molecular motor dynein to travel along microtubules. The circovirus capsid subunit enhances microtubular acetylation, and N-terminal residues 42 to 100 directly interact with the dynein IC1 subunit during retrograde transport. These findings highlight a mechanism whereby circoviruses recruit dynein for transport to the nucleus via the dynein/microtubule machinery.

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