Intracellular neuronal calcium sensor proteins: a family of EF-hand calcium-binding proteins in search of a function

Braunewell, Karl-Heinz; Gundelfinger, Eckart D.

doi:10.1007/s004410051207

Cited by 245 publications

(218 citation statements)

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“…Structural, biochemical, and biophysical characterization of CaM complexed with these proteins or short peptides derived from within revealed that the myr group is involved in CaM binding, suggesting that the myr group is not only important for membrane targeting but also for mediating protein-protein interactions. Membrane association and dissociation of myristoylated proteins are often regulated by intracellular Ca 2ϩ signaling through a Ca 2ϩ -myr switch (52-54), which alters their intracellular localization from the cytosol to the membrane through Ca 2ϩ binding (55). However, intracellular targeting of Ca 2ϩ nonsensing proteins like MARCKS, CAP-23/NAP-22, and Nef is regulated by CaM binding.…”

Section: Discussionmentioning

confidence: 99%

“…Membrane association and dissociation of myristoylated proteins are often regulated by intracellular Ca 2ϩ signaling through a "Ca 2ϩ -myr switch." Some examples include the Ca 2ϩ sensor proteins recoverin (52), neurocalcin (53), and S-modulin (54), which alter their intracellular localization from the cytosol to the membrane through Ca 2ϩ binding (55). In this report, we present structural, biochemical, and biophysical data on the interactions between myr(ϩ)MA and CaM.…”

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confidence: 99%

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Binding of Calmodulin to the HIV-1 Matrix Protein Triggers Myristate Exposure

Ghanam

Fernandez

Fledderman

et al. 2010

Journal of Biological Chemistry

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Steady progress has been made in defining both the viral and cellular determinants of retroviral assembly and release. Although it is widely accepted that targeting of the Gag polypeptide to the plasma membrane is critical for proper assembly of HIV-1, the intracellular interactions and trafficking of Gag to its assembly sites in the infected cell are poorly understood. HIV-1 Gag was shown to interact and co-localize with calmodulin (CaM), a ubiquitous and highly conserved Ca 2؉ -binding protein expressed in all eukaryotic cells, and is implicated in a variety of cellular functions. Binding of HIV-1 Gag to CaM is dependent on calcium and is mediated by the N-terminally myristoylated matrix (myr(؉)MA) domain. Herein, we demonstrate that CaM binds to myr(؉)MA with a dissociation constant (K d ) of ϳ2 M and 1:1 stoichiometry. Strikingly, our data revealed that CaM binding to MA induces the extrusion of the myr group. However, in contrast to all known examples of CaM-binding myristoylated proteins, our data show that the myr group is exposed to solvent and not involved in CaM binding. The interactions between CaM and myr(؉)MA are endothermic and entropically driven, suggesting that hydrophobic contacts are critical for binding. As revealed by NMR data, both CaM and MA appear to engage substantial regions and/or undergo significant conformational changes upon binding. We believe that our findings will provide new insights on how Gag may interact with CaM during the HIV replication cycle.Gag is the major structural protein encoded by HIV-1 and contains all of the viral elements required to drive virus assembly (1-3). HIV-1 Gag targeting to the plasma membrane (PM) 2 is critical for proper and efficient assembly to produce progeny virions (1, 3-9). During virus maturation, Gag is cleaved into myristoylated matrix (myr(ϩ)MA), capsid, and nucleocapsid proteins, inducing major morphological reorganization of the virus (1, 2, 4, 5, 10). In many cell types, HIV-1 Gag budding and assembly has been shown to occur predominantly on the PM (4 -9, 11-18). Gag binding to the PM is mediated by the MA domain and enhanced by multimerization. Proper assembly and efficient binding of Gag to the PM requires a myristyl (myr) group as a membrane anchor and a cluster of basic residues localized within the N-terminal domain to facilitate interactions with acidic phospholipids (1,2,19,20).Steady progress has been made in defining both the viral and cellular determinants of HIV-1 assembly and release (6). However, the trafficking pathway used by Gag to reach assembly sites in the infected cell is poorly understood. Studies by Freed, Ono, and co-workers (21-23) demonstrated that the ultimate localization of HIV-1 Gag at virus assembly sites is dependent on phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P 2 ), a cellular factor localized at the inner leaflet of the PM (24 -26). Our structural studies revealed that PI(4,5)P 2 binds directly to HIV-1 MA, inducing a conformational change that triggers myr exposure (27). In addition to PI(4,5)P 2 ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Binding of Calmodulin to the HIV-1 Matrix Protein Triggers Myristate Exposure

Ghanam

Fernandez

Fledderman

et al. 2010

Journal of Biological Chemistry

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“…Thus, stimulation of yeast cells by pheromones or other extracellular stimuli lead to an increase in intracellular Ca 2ϩ levels (10,11) sensed by Ca 2ϩ -binding proteins belonging to the EF-hand superfamily (12). In S. pombe, a total of 23 genes specifies EF-hand-containing Ca 2ϩ -binding proteins, including cam1 (calmodulin) (13), cnb1 (calcineurin B) (14), and the recently characterized ncs1 gene (Ncs1p) (15), belonging to the neuronal calcium sensor (NCS) 2 family (16) expressed mostly in the central nervous system (17,18).…”

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Neuronal Calcium Sensor-1 (Ncs1p) Is Up-regulated by Calcineurin to Promote Ca2+ Tolerance in Fission Yeast

Hamasaki-Katagiri

Ames

2010

Journal of Biological Chemistry

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) regulates signaling processes in the fission yeast, Schizosaccharomyces pombe (reviewed in Refs. 1-3), as it does in mammalian cells (reviewed in Ref. 4). Fission yeast contains ion channels (5, 6) and transporters (7-9) homologous to those involved in regulating Ca 2ϩ entry and signal transduction in excitable cells. Thus, stimulation of yeast cells by pheromones or other extracellular stimuli lead to an increase in intracellular Ca 2ϩ levels (10, 11) sensed by Ca 2ϩ -binding proteins belonging to the EF-hand superfamily (12). In S. pombe, a total of 23 genes specifies EF-hand-containing Ca 2ϩ -binding proteins, including cam1 (calmodulin) (13), cnb1 (calcineurin B) (14), and the recently characterized ncs1 gene (Ncs1p) (15), belonging to the neuronal calcium sensor (NCS) 2 family (16) expressed mostly in the central nervous system (17, 18).The primary sequence of S. pombe Ncs1p is Ͼ50% identical to neuronal homologs of the NCS branch of the EF-hand superfamily (19,20). Recoverin, the most intensively studied NCS protein, serves as a Ca 2ϩ sensor in retinal rod and cone cells where it controls the desensitization of rhodopsin (21-24). The NCS family also includes neuronal Ca 2ϩ sensors such as neurocalcin (25), hippocalcin (26), and frequenin (27), as well as the budding yeast homolog, Frq1 (28). All members of the NCS family have around 200 amino acid residues, contain N-terminal myristoylation, and possess four EF-hands.Three-dimensional structures are now known for many NCS proteins, including recoverin (29, 30), frequenin (31), Frq1 (32), neurocalcin (33), and guanylate cyclase activator proteins (34, 35). The Ca 2ϩ -bound forms of these proteins all share a common fold with four EF-hands arranged in a tandem array, with an exposed N-terminal myristoyl group. Binding of Ca 2ϩ to recoverin leads to extrusion of its myristoyl group such that many hydrophobic residues become exposed for target recognition (30, 36). The Ca 2ϩ -induced exposure of the myristoyl group, termed the Ca 2ϩ -myristoyl switch, enables recoverin to bind to membrane targets only at high Ca 2ϩ levels (37, 38). NCS proteins interact with and regulate many different physiological targets. Recoverin binds specifically and regulates rhodopsin kinase (23), whereas the guanylate cyclase activator proteins specifically regulate retinal guanylate cyclases (39, 40). NCS-1 and yeast Frq1 activate phosphatidylinositol 4-kinase important for secretion from the Golgi (28). Hippocalcin and VILIP proteins regulate guanylate cyclase and nicotinamide acetylcholine receptors implicated in synaptic plasticity (41). KChIPs (42), hippocalcin (43), and NCS-1 (44) all bind and regulate various ion channels and thus serve as Ca 2ϩ sensors that control membrane excitability. The mechanism of target regulation in each case is not understood, and it remains unclear how the structurally similar NCS proteins are able to specifically bind and regulate so many different target proteins.Yeast genetics is a powerful tool for dissecting NCS protein interactions in signa...

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“…NCS-1 belongs to the intracellular neuronal calcium sensor family of EF-hand calcium binding proteins [17] . Loss-of-function of NCS-1 does not restore IT, whereas NCS-1 overexpression enhances IT performance levels, and produces a memory (< 18 h) with slower extinction [3] .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the long-term memory for thermosensation regulated by neuronal calcium sensor-1 in Caenorhabditis elegans

Wang

2008

Neurosci. Bull.

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Objective To evaluate whether the thermotaxis tracking model is suitable for assessing long-term memory (LTM) in the nematode Caenorhabditis elegans. Methods Animals were trained at 20 o C overnight in presence of food. The percentage of animals performing isothermal tracking (IT) behavior was measured at different time intervals after the training. Results The percentage of animals performing IT behavior, the numbers of body bends inside and outside the training temperature, and the expression patterns of AFD and AIY neurons were similar to those in control animals at 36 and 48 h after training; whereas when extending to 60, 72, and 84 h, locomotory behavior defects were observed in the assayed animals, suggesting that this thermal tracking model is feasible for analyzing LTM at 36 and 48 h after training. Moreover, the percentage of animals performing IT behavior was reduced at 18, 36, and 48 h after training in neuronal calcium sensor-1 gene (nsc-1) mutant animals compared with that in wild-type N2 animals. In addition, exposure to plumbum (Pb) significantly repressed the LTM at 18, 36, and 48 h after training in both wild-type N2 and ncs-1 mutant animals. Conclusion The thermotaxis tracking model is suitable for evaluating the LTM regulated by NCS-1, and can be employed for elucidating regulatory functions of specific genes or effects of stimuli on memory in C. elegans.

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Intracellular neuronal calcium sensor proteins: a family of EF-hand calcium-binding proteins in search of a function

Cited by 245 publications

References 110 publications

Binding of Calmodulin to the HIV-1 Matrix Protein Triggers Myristate Exposure

Binding of Calmodulin to the HIV-1 Matrix Protein Triggers Myristate Exposure

Neuronal Calcium Sensor-1 (Ncs1p) Is Up-regulated by Calcineurin to Promote Ca2+ Tolerance in Fission Yeast

Evaluation of the long-term memory for thermosensation regulated by neuronal calcium sensor-1 in Caenorhabditis elegans

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