Abstract
Neuronal calcium sensor (NCS) proteins, a sub-branch of the EF-hand superfamily, are expressed in the brain and retina where they transduce calcium signals and are genetically linked to degenerative diseases. The amino acid sequences of NCS proteins are highly conserved but their physiological functions are quite distinct. Retinal recoverin and guanylate cyclase activating proteins (GCAPs) both serve as calcium sensors in retinal rod cells, neuronal frequenin (NCS1) modulates synaptic activity and neuronal secretion, K+ channel interacting proteins (KChIPs) regulate ion channels to control neuronal excitability, and DREAM (KChIP3) is a transcriptional repressor that regulates neuronal gene expression. Here we review the molecular structures of myristoylated forms of NCS1, recoverin, and GCAP1 that all look very different, suggesting that the sequestered myristoyl group helps to refold these highly homologous proteins into very different structures. The molecular structure of NCS target complexes have been solved for recoverin bound to rhodopsin kinase (RK), NCS-1 bound to phosphatidylinositol 4-kinase, and KChIP1 bound to A-type K+ channels. We propose that N-terminal myristoylation is critical for shaping each NCS family member into a different structure, which upon Ca2+-induced extrusion of the myristoyl group exposes a unique set of previously masked residues that interact with a particular physiological target.
Highlights
We propose that N-terminal myristoylation is critical for shaping each neuronal calcium sensor (NCS) family member into a different structure, which upon Ca2+-induced extrusion of the myristoyl group exposes a unique set of previously masked residues that interact with a particular physiological target
Non-conserved residues are are expressed in the brain and spinal cord such as neurocalcin found near the C-terminus and linker between EF3 and EF4 that (Hidaka and Okazaki, 1993), frequenin (NCS1) (Pongs et al, both interact with target proteins/membranes and may play a role 1993; McFerran et al, 1998), visinin-like proteins (Bernstein et al, in target specificity. 1999; Braunewell and Klein-Szanto, 2009), K+ channel interacting The structurally similar NCS proteins have remarkably differproteins (KChIPs) (An et al, 2000), DREAM/calsenilin (Buxbaum ent physiologic functions (Table 1)
We suggest that each Ca2+-myristoyl switch protein may adopt a distinct structure because its N-terminal myristoyl group associates with patches of hydrophobic residues that are unique to that protein
Summary
Edited by: Neuronal calcium sensor (NCS) proteins, a sub-branch of the EF-hand superfamily, are. Centro Nacional de Biotecnología, Spain Robert Kretsinger, University of Virginia, USA expressed in the brain and retina where they transduce calcium signals and are genetically linked to degenerative diseases. The amino acid sequences of NCS proteins are highly conserved but their physiological functions are quite distinct. Retinal recoverin and guanylate cyclase activating proteins (GCAPs) both serve as calcium sensors in retinal rod cells, neuronal frequenin (NCS1) modulates synaptic activity and neuronal secretion, K+ channel interacting proteins (KChIPs) regulate ion channels to control neuronal. C INTRODUCTION A Intracellular calcium (Ca2+) regulates a variety of neuronal signal transduction processes in the brain and retina (Berridge et al, 2000; Augustine et al, 2003). The amino acid sequences of NCS proteins are highly conserved from
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