Arc Oligomerization Is Regulated by CaMKII Phosphorylation of the GAG Domain: An Essential Mechanism for Plasticity and Memory Formation

Mol Cell. 2019 Jul 11;75(1):13-25.e5. doi: 10.1016/j.molcel.2019.05.004. Epub 2019 May 28.

Abstract

Arc is a synaptic protein essential for memory consolidation. Recent studies indicate that Arc originates in evolution from a Ty3-Gypsy retrotransposon GAG domain. The N-lobe of Arc GAG domain acquired a hydrophobic binding pocket in higher vertebrates that is essential for Arc's canonical function to weaken excitatory synapses. Here, we report that Arc GAG also acquired phosphorylation sites that can acutely regulate its synaptic function. CaMKII phosphorylates the N-lobe of the Arc GAG domain and disrupts an interaction surface essential for high-order oligomerization. In Purkinje neurons, CaMKII phosphorylation acutely reverses Arc's synaptic action. Mutant Arc that cannot be phosphorylated by CaMKII enhances metabotropic receptor-dependent depression in the hippocampus but does not alter baseline synaptic transmission or long-term potentiation. Behavioral studies indicate that hippocampus- and amygdala-dependent learning requires Arc GAG domain phosphorylation. These studies provide an atomic model for dynamic and local control of Arc function underlying synaptic plasticity and memory.

Keywords: Arc; CAMKII; capsid; evolution; learning and memory; phosphorylation; polymerization; synapse plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amygdala / cytology
  • Amygdala / metabolism
  • Animals
  • Binding Sites
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / chemistry
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Gene Knock-In Techniques
  • HEK293 Cells
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Long-Term Potentiation / physiology*
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Molecular
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Purkinje Cells / cytology
  • Purkinje Cells / metabolism*
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Synapses / physiology
  • Synaptic Transmission

Substances

  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • activity regulated cytoskeletal-associated protein
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2