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Molecular structure and target recognition of neuronal calcium sensor proteins.

Ames JB, Lim S, Ikura M - Front Mol Neurosci (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of California, Davis CA, USA.

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 Ca(2+)-induced extrusion of the myristoyl group exposes a unique set of previously masked residues that interact with a particular physiological target.

No MeSH data available.


Related in: MedlinePlus

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.
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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.

Mentions: The x-ray crystal structure of recombinant unmyristoylated recoverin (Flaherty et al., 1993; Weiergraber et al., 2003) showed it to contain a compact array of EF-hand motifs, in contrast to the dumbbell shape of calmodulin (Babu et al., 1988) and troponin C (Herzberg and James, 1988). The four EF-hands are organized into two domains: the first EF-hand, EF-1 (residues 27–56, colored green in Figures 1 and 3), interacts with EF-2 (residues 63–92, red) to form the N-terminal domain, and EF-3 (residues 101–130, cyan), and EF-4 (residues 148–177, yellow) form the C-terminal domain. The linker between the two domains is U-shaped rather than α-helical. Ca2+ is bound to EF-3 and Sm3+ (used to derive phases) is bound to EF-2. The other two EF hands possess novel features that prevent ion binding. EF-1 is disrupted by a Cys-Pro sequence in the binding loop. EF-4 contains an internal salt bridge in the binding loop that competes with Ca2+ binding. Myristoylated recoverin, the physiologically active form has thus far eluded crystallization.


Molecular structure and target recognition of neuronal calcium sensor proteins.

Ames JB, Lim S, Ikura M - Front Mol Neurosci (2012)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3275791&req=5

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.
Mentions: The x-ray crystal structure of recombinant unmyristoylated recoverin (Flaherty et al., 1993; Weiergraber et al., 2003) showed it to contain a compact array of EF-hand motifs, in contrast to the dumbbell shape of calmodulin (Babu et al., 1988) and troponin C (Herzberg and James, 1988). The four EF-hands are organized into two domains: the first EF-hand, EF-1 (residues 27–56, colored green in Figures 1 and 3), interacts with EF-2 (residues 63–92, red) to form the N-terminal domain, and EF-3 (residues 101–130, cyan), and EF-4 (residues 148–177, yellow) form the C-terminal domain. The linker between the two domains is U-shaped rather than α-helical. Ca2+ is bound to EF-3 and Sm3+ (used to derive phases) is bound to EF-2. The other two EF hands possess novel features that prevent ion binding. EF-1 is disrupted by a Cys-Pro sequence in the binding loop. EF-4 contains an internal salt bridge in the binding loop that competes with Ca2+ binding. Myristoylated recoverin, the physiologically active form has thus far eluded crystallization.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of California, Davis CA, USA.

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 Ca(2+)-induced extrusion of the myristoyl group exposes a unique set of previously masked residues that interact with a particular physiological target.

No MeSH data available.


Related in: MedlinePlus