Arc self-association and formation of virus-like capsids are mediated by an N-terminal helical coil motif.
Amino Acid Motifs
/ genetics
Animals
Capsid Proteins
/ genetics
Cryoelectron Microscopy
Crystallography, X-Ray
Cytoskeletal Proteins
/ genetics
Drosophila Proteins
/ genetics
Humans
Nerve Tissue Proteins
/ genetics
Neuronal Plasticity
/ genetics
Neurons
/ metabolism
Protein Conformation
Protein Domains
/ genetics
RNA
/ genetics
Sequence Homology, Amino Acid
Signal Transduction
/ genetics
Virion
/ genetics
activity-regulated cytoskeleton-associated protein (Arc)/coiled-coil interactions/protein oligomerization
retrovirus-like capsid/synaptic plasticity
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
revised:
13
10
2020
received:
03
09
2020
accepted:
26
10
2020
pubmed:
12
11
2020
medline:
22
7
2021
entrez:
11
11
2020
Statut:
ppublish
Résumé
Activity-regulated cytoskeleton-associated protein (Arc) is a protein interaction hub with diverse roles in intracellular neuronal signaling, and important functions in neuronal synaptic plasticity, memory, and postnatal cortical development. Arc has homology to retroviral Gag protein and is capable of self-assembly into virus-like capsids implicated in the intercellular transfer of RNA. However, the molecular basis of Arc self-association and capsid formation is largely unknown. Here, we identified a 28-amino-acid stretch in the mammalian Arc N-terminal (NT) domain that is necessary and sufficient for self-association. Within this region, we identified a 7-residue oligomerization motif, critical for the formation of virus-like capsids. Purified wild-type Arc formed capsids as shown by transmission and cryo-electron microscopy, whereas mutant Arc with disruption of the oligomerization motif formed homogenous dimers. An atomic-resolution crystal structure of the oligomerization region peptide demonstrated an antiparallel coiled-coil interface, strongly supporting NT-NT domain interactions in Arc oligomerization. The NT coil-coil interaction was also validated in live neurons using fluorescence lifetime FRET imaging, and mutation of the oligomerization motif disrupted Arc-facilitated endocytosis. Furthermore, using single-molecule photobleaching, we show that Arc mRNA greatly enhances higher-order oligomerization in a manner dependent on the oligomerization motif. In conclusion, a helical coil in the Arc NT domain supports self-association above the dimer stage, mRNA-induced oligomerization, and formation of virus-like capsids. DATABASE: The coordinates and structure factors for crystallographic analysis of the oligomerization region were deposited at the Protein Data Bank with the entry code 6YTU.
Substances chimiques
Capsid Proteins
0
Cytoskeletal Proteins
0
Drosophila Proteins
0
Nerve Tissue Proteins
0
a protein, Drosophila
0
activity regulated cytoskeletal-associated protein
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2930-2955Informations de copyright
© 2020 Federation of European Biochemical Societies.
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