Structural basis for the interaction of unstructured neuron specific substrates neuromodulin and neurogranin with Calmodulin

Sci Rep. 2013;3:1392. doi: 10.1038/srep01392.

Abstract

Neuromodulin (Nm) and neurogranin (Ng) are neuron-specific substrates of protein kinase C (PKC). Their interactions with Calmodulin (CaM) are crucial for learning and memory formation in neurons. Here, we report the structure of IQ peptides (24aa) of Nm/Ng complexed with CaM and their functional studies with full-length proteins. Nm/Ng and their respective IQ peptides are intrinsically unstructured; however, upon binding with CaM, IQ motifs adopt a helical conformation. Ser41 (Ser36) of Nm (Ng) is located in a negatively charged pocket in the apo CaM and, when phosphorylated, it will repel Nm/Ng from CaM. These observations explain the mechanism by which PKC-induced Ser phosphorylation blocks the association of Nm/Ng with CaM and interrupts several learning- and memory-associated functions. Moreover, the present study identified Arg as a key CaM interacting residue from Nm/Ng. This residue is crucial for CaM-mediated function, as evidenced by the inability of the Ng mutant (Arg-to-Ala) to potentiate synaptic transmission in CA1 hippocampal neurons.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Calmodulin / metabolism*
  • GAP-43 Protein / chemistry*
  • GAP-43 Protein / metabolism
  • Kinetics
  • Models, Molecular
  • Molecular Sequence Data
  • Neurogranin / chemistry*
  • Neurogranin / metabolism
  • Neurons / metabolism*
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Unfolding
  • Rats
  • Sequence Alignment
  • Synaptic Transmission

Substances

  • Calmodulin
  • GAP-43 Protein
  • Neurogranin

Associated data

  • PDB/4E50
  • PDB/4E53