Structural basis for the interaction of unstructured neuron specific substrates neuromodulin and neurogranin with Calmodulin. Sci Rep 2013;3:1392
Date
03/07/2013Pubmed ID
23462742Pubmed Central ID
PMC3589724DOI
10.1038/srep01392Scopus ID
2-s2.0-84875147681 (requires institutional sign-in at Scopus site) 52 CitationsAbstract
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.
Author List
Kumar V, Chichili VP, Zhong L, Tang X, Velazquez-Campoy A, Sheu FS, Seetharaman J, Gerges NZ, Sivaraman JAuthor
Nashaat Gerges PhD Chair, Professor in the School of Pharmacy Administration department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid MotifsAmino Acid Sequence
Animals
Calmodulin
GAP-43 Protein
Kinetics
Models, Molecular
Molecular Sequence Data
Neurogranin
Neurons
Nuclear Magnetic Resonance, Biomolecular
Protein Binding
Protein Structure, Secondary
Protein Unfolding
Rats
Sequence Alignment
Synaptic Transmission
