Stimulus-evoked ERK-dependent phosphorylation of activity-regulated cytoskeleton-associated protein (Arc) regulates its neuronal subcellular localization

Nikolaienko, Oleksii; Eriksen, Maria Steene; Patil, Sudarshan; Bito, Haruhiko; Bramham, Clive R.

doi:10.1016/j.neuroscience.2017.07.026

Cited by 40 publications

(47 citation statements)

References 52 publications

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“…The complete explanation to this question will likely include the revelation of an intricate set of protein PTMs that act to confer different molecular and functional specificity to Arc as well as potential subcellular distribution into distinct protein complexes. To date, only a small number of reports have provided evidence for the influence of PTMs, which includes ubiquitination 15 , 37 , sumoylation 50 , 51 , as well as phosphorylation 52 , 53 , on Arc biochemistry and function. In this study, we uncovered a role for lysine acetylation in the control of Arc protein stability.…”

Section: Discussionmentioning

confidence: 99%

Chemogenomic analysis reveals key role for lysine acetylation in regulating Arc stability

et al. 2017

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The role of Arc in synaptic plasticity and memory consolidation has been investigated for many years with recent evidence that defects in the expression or activity of this immediate-early gene may also contribute to the pathophysiology of brain disorders including schizophrenia and fragile X syndrome. These results bring forward the concept that reversing Arc abnormalities could provide an avenue to improve cognitive or neurological impairments in different disease contexts, but how to achieve this therapeutic objective has remained elusive. Here, we present results from a chemogenomic screen that probed a mechanistically diverse library of small molecules for modulators of BDNF-induced Arc expression in primary cortical neurons. This effort identified compounds with a range of influences on Arc, including promoting its acetylation—a previously uncharacterized post-translational modification of this protein. Together, our data provide insights into the control of Arc that could be targeted to harness neuroplasticity for clinical applications.

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Section: Discussionmentioning

confidence: 99%

Chemogenomic analysis reveals key role for lysine acetylation in regulating Arc stability

et al. 2017

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“…), and rat ARC (pGEX‐4T‐3‐Arc) (Nikolaienko et al . ) have been described previously. The constructs encoding EGFP (pEGFP‐N1) and mCherry (pmCherry‐C1) were from Takara Bio (Mountain View, CA, USA; RRID:SCR_003960).…”

Section: Methodsmentioning

confidence: 99%

Structure of monomeric full‐length ARC sheds light on molecular flexibility, protein interactions, and functional modalities

Hallin

Eriksen

Baryshnikov

et al. 2018

Journal of Neurochemistry

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The activity-regulated cytoskeleton-associated protein (ARC) is critical for long-term synaptic plasticity and memory formation. Acting as a protein interaction hub, ARC regulates diverse signalling events in postsynaptic neurons. A protein interaction site is present in the ARC C-terminal domain (CTD), a bilobar structure homologous to the retroviral Gag capsid domain. We hypothesized that detailed knowledge of the three-dimensional molecular structure of monomeric full-length ARC is crucial to understand its function; therefore, we set out to determine the structure of ARC to understand its various functional modalities. We purified recombinant ARC and analyzed its structure using small-angle X-ray scattering and synchrotron radiation circular dichroism spectroscopy. Monomeric full-length ARC has a compact, closed structure, in which the oppositely charged N-terminal domain (NTD) and CTD are juxtaposed, and the flexible linker between them is not extended. The modeled structure of ARC is supported by intramolecular live-cell Förster resonance energy transfer imaging in rat hippocampal slices. Peptides from several postsynaptic proteins, including stargazin, bind to the N-lobe, but not to the C-lobe, of the bilobar CTD. This interaction does not induce large-scale conformational changes in the CTD or flanking unfolded regions. The ARC NTD contains long helices, predicted to form an anti-parallel coiled coil; binding of ARC to phospholipid membranes requires the NTD. Our data support a role for the ARC NTD in oligomerization as well as lipid membrane binding. The findings have important implications for the structural organization of ARC with respect to distinct functions, such as postsynaptic signal transduction and virus-like capsid formation. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

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“…The original polylinker sequence between the NheI and XhoI restriction sites was replaced with a custom polylinker containing a Kozak sequence, start and stop codons, as well as additional restriction sites to facilitate subcloning (5'-GCTAGC-ACTAGT-ACC-ATG-ACCGGT-GCGATCGC-A-GGATCC-GCGGCCGC-A-TCCGGA-TTAATTAA-A-TAA-CTCGAG-3'). The constructs encoding mTurquoise2 (pLifeAct-mTurquoise2, Addgene (RRID:SCR_002037) plasmid #36201) (Goedhart et al 2012), YPet (pCEP4YPet-MAMM, Addgene plasmid #14032) (Nguyen and Daugherty 2005), P2A sequence (pAAV-hSyn1-mRuby2-GSG-P2A-GCaMP6s-WPRE-pA, Addgene plasmid #50942) (Rose et al 2016), and rat ARC (pGEX-4T-3-Arc) (Nikolaienko et al 2017a) have been described previously. The constructs encoding EGFP (pEGFP-N1) and mCherry (pmCherry-C1) were from Takara Bio (Mountain View, CA, USA).…”

Section: Fret Experimentsmentioning

confidence: 99%

Structure of monomeric full-length ARC sheds light on molecular flexibility, protein interactions, and functional modalities

Hallin

Eriksen

Baryshnikov

et al. 2018

Preprint

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The activity-regulated cytoskeleton-associated protein (ARC) is critical for long-term synaptic plasticity and memory formation. Acting as a protein interaction hub, ARC regulates diverse signalling events in postsynaptic neurons. A protein interaction site is present in the ARC C-terminal domain (CTD), a bilobar structure homologous to the retroviral Gag capsid domain. However, knowledge of the 3-dimensional structure of full-length ARC is required to elucidate its molecular function. We purified recombinant monomeric full-length ARC and analyzed its structure using small-angle X-ray scattering and synchrotron radiation circular dichroism spectroscopy. In solution, monomeric ARC has a compact, closed structure, in which the oppositely charged N-terminal domain (NTD) and CTD are juxtaposed, and the flexible linker between them is not extended. The modelled structure of ARC is supported by intramolecular live-cell FRET imaging in rat hippocampal slices. Peptides from several postsynaptic proteins, including stargazin, bind to the N-lobe, but not to the C-lobe, of the bilobar CTD. This interaction does not induce large-scale conformational changes in the CTD or flanking unfolded regions. The ARC NTD contains long helices, predicted to form an antiparallel coiled coil; binding of ARC to phospholipid membranes requires the NTD. Our data support a role for the ARC NTD in oligomerization as well as lipid membrane binding. These findings have important implications for the structural organization of ARC in distinct functional modalities, such as postsynaptic signal transduction and virus-like capsid formation.

show abstract

Stimulus-evoked ERK-dependent phosphorylation of activity-regulated cytoskeleton-associated protein (Arc) regulates its neuronal subcellular localization

Cited by 40 publications

References 52 publications

Chemogenomic analysis reveals key role for lysine acetylation in regulating Arc stability

Chemogenomic analysis reveals key role for lysine acetylation in regulating Arc stability

Structure of monomeric full‐length ARC sheds light on molecular flexibility, protein interactions, and functional modalities

Structure of monomeric full-length ARC sheds light on molecular flexibility, protein interactions, and functional modalities

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