title: Structural basis for the interaction of unstructured neuron specific substrates neuromodulin and neurogranin with Calmodulin.
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.
authors: Department of Biological Sciences, National University of Singapore, Singapore.
authors: Veerendra
authors: V
authors: Kumar
authors: Vishnu Priyanka Reddy
authors: VP
authors: Chichili
authors: Ling
authors: L
authors: Zhong
authors: Xuhua
authors: X
authors: Tang
authors: Adrian
authors: A
authors: Velazquez-Campoy
authors: Fwu-Shan
authors: FS
authors: Sheu
authors: J
authors: J
authors: Seetharaman
authors: Nashaat Z
authors: NZ
authors: Gerges
authors: J
authors: J
authors: Sivaraman
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002147:Calmodulin / Q000378:metabolism*; D019922:GAP-43 Protein / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051579:Neurogranin / Q000737:chemistry* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D051381:Rats; D016415:Sequence Alignment; D009435:Synaptic Transmission
chemical_list: D002147:Calmodulin; D019922:GAP-43 Protein; D051579:Neurogranin