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Review
, 1820 (8), 1205-13

Molecular Structure and Target Recognition of Neuronal Calcium Sensor Proteins

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Review

Molecular Structure and Target Recognition of Neuronal Calcium Sensor Proteins

James B Ames et al. Biochim Biophys Acta.

Abstract

Background: Neuronal calcium sensor (NCS) proteins, a sub-branch of the calmodulin 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) modulate 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.

Scope of review: 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, NCS-1 bound to phosphatidylinositol 4-kinase, and KChIP1 bound to A-type K+ channels.

Major conclusions: We propose the idea that N-terminal myristoylation is critical for shaping each NCS family member into a unique structure, which upon Ca2+-induced extrusion of the myristoyl group exposes a unique set of previously masked residues, thereby exposing a distinctive ensemble of hydrophobic residues to associate specifically with a particular physiological target. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signaling.

Figures

FIGURE 1
FIGURE 1
Amino acid sequence alignment of selected NCS proteins (sequence numbering is for S. pombe NCS1). Secondary structure elements (helices and strands), EF-hand motifs (EF1 green, EF2 red, EF3 cyan and EF4 yellow), and residues that interact with the myristoyl group (highlighted magenta) are indicated. Swiss Protein Database accession numbers are Q09711 (S. pombe Ncs1), Q06389 (S. cerevisiae Frq1), P21457 (bovine recoverin), and P43080 (human GCAP1).
FIGURE 2
FIGURE 2
Schematic diagram of calcium-myristoyl switch in recoverin. The binding of two Ca2+ ions promotes the extrusion of the myristoyl group and exposure of other hydrophobic residues (marked by the shaded oval). This figure was adapted from and originally published by [61].
FIGURE 3
FIGURE 3
Three-dimensional structures of myristoylated recoverin with 0 Ca2+ bound (A), 1 Ca2+ bound (B) and 2 Ca2+ bound (C). The first step of the mechanism involves the binding of Ca2+ to EF-3 that causes minor structural changes within the EF-hand that sterically promote a 45° swiveling of the two domains, resulting in a partial unclamping of the myristoyl group and a dramatic rearrangement at the domain interface. The resulting altered interaction between EF-2 and EF-3 facilitates the binding of a second Ca2+ to the protein at EF-2 in the second step, which causes structural changes within the N-terminal domain that directly lead to the ejection of the fatty acyl group.
FIGURE 4
FIGURE 4
Main chain structure (A) and space-filling representation (B) of myristoylated recoverin bound to oriented lipid bilayers determined by solid-state NMR [70]. Hydrophobic residues are yellow, bound Ca2+ ions are orange, and charged residues are red and blue.
FIGURE 5
FIGURE 5
Main chain structures of Ca2+-free myrisoylated NCS1 (PDB ID: 212e) (A), recoverin (PDB ID: 1iku) (B), and GCAP1 (PDB ID: 2r2i) (C). Close-up views of the myristate binding pocket in NCS1 (D) and recoverin (E). EF-hands and myristoyl group (magenta) are colored as defined in Fig. 1. Adapted from and originally published by [73].
FIGURE 6
FIGURE 6
Space-filling representations of the Ca2+-bound structures of recoverin (A), frequenin (B), neurocalcin (C) and KChIP1 (D). Exposed hydrophobic residues are yellow, neutral residues are white and charge residues are red and blue.
FIGURE 7
FIGURE 7
Ribbon diagrams illustrating intermolecular interactions for Recoverin bound to RK25 (A), KChIP1 bound to Kv4.32 (B), NCS1 (N-domain) bound to Pik1(111-151) (C), NCS1 (C-domain) bound to Pik1(111-151) (D), and space-filling view of NCS1 bound to Pik1(111-151) (E). In each case, a target helix (magenta) is inserted in groove formed by the helices of the EF-hands. The intermolecular interactions are mostly hydrophobic as described in the text.
FIGURE 8
FIGURE 8
Schematic diagram of calcium-myristoyl switch coupled to target regulation illustrated for NCS1 (A) and recoverin (B). Adapted from and originally published by [73].

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