Dimerization of Guanylyl Cyclase-activating Protein and a Mechanism of Photoreceptor Guanylyl Cyclase Activation

Olshevskaya, Elena V.; Ermilov, A. Yu.; Dizhoor, Alexander M.

doi:10.1074/jbc.274.36.25583

Cited by 83 publications

(80 citation statements)

References 41 publications

(57 reference statements)

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“…Recent studies show that the catalysis of the cyclic GMP formation by ROS-GC1 occurs at a dimer interface (52) and that its activation by GCAPs or S100 involves dimerization step (29,30). Thus, ROS-GC1 requires dimerization for effective catalytic activity (29,30).…”

Section: Discussionmentioning

confidence: 99%

“…Analyses of the results presented above indicate that under all tested experimental conditions, the amount of cyclic GMP formed by the ERTfDCM mutant is lower than that formed by wt-rROS-GC1. Earlier studies have indicated that the active state of ROS-GC1 is represented by its dimeric form (29,30). To determine if the impaired functioning of the cyclase is a result of disturbed dimer formation, the dimerization of the wt and mutated ROS-GC1 was tested by crosslinking and gel-filtration chromatography.…”

Section: Hek293 and Cos Cells Expression Systems Are Comparable It Wmentioning

confidence: 99%

“…The cyclase must be in a dimeric form to be active (29,30). The identity of the dimerization domain is not known.…”

mentioning

confidence: 99%

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Impairment of the Rod Outer Segment Membrane Guanylate Cyclase Dimerization in A Cone−Rod Dystrophy Results in Defective Calcium Signaling

et al. 2000

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Rod outer segment membrane guanylate cyclase1 (ROS-GC1) is the original member of the membrane guanylate cyclase subfamily whose distinctive feature is that it transduces diverse intracellularly generated Ca 2+ signals in the sensory neurons. In the vertebrate retinal neurons, ROS-GC1 is pivotal for the operations of phototransduction and, most likely, of the synaptic activity. The phototransduction-and the synapse-linked domains are separate, and they are located in the intracellular region of ROS-GC1. These domains sense Ca 2+ signals via Ca 2+ -binding proteins. These proteins are ROS-GC activating proteins, GCAPs. GCAPs control ROS-GC1 activity through two opposing regulatory modes. In one mode, at nanomolar concentrations of Ca 2+ , the GCAPs activate the cyclase and as the Ca 2+ concentrations rise, the cyclase is progressively inhibited. This mode operates in phototransduction via two GCAPs: 1 and 2. The second mode occurs at micromolar concentrations of Ca 2+ via S100 . Here, the rise of Ca 2+ concentrations progressively stimulates the enzyme. This mode is linked with the retinal synaptic activity. In both modes, the final step in Ca 2+ signal transduction involves ROS-GC dimerization, which causes the cyclase activation. The identity of the dimerization domain is not known. A heterozygous, triple mutation -E786D, R787C, T788M-in ROS-GC1 has been connected with autosomal cone-rod dystrophy in a British family. The present study shows the biochemical consequences of this mutation on the phototransduction-and the synapse-linked components of the cyclase. (1) It severely damages the intrinsic cyclase activity. (2) It significantly raises the GCAP1-and GCAP2-dependent maximal velocity of the cyclase, but this compensation, however, is not sufficient to override the basal cyclase activity. (3) It converts the cyclase into a form that only marginally responds to S100 . The mutant produces insufficient amounts of the cyclic GMP needed to drive the machinery of phototransduction and of the retinal synapse at an optimum level. The underlying cause of the breakdown of both types of machinery is that, in contrast to the native ROS-GC1, the mutant cyclase is unable to change from its monomeric to the dimeric form, the form required for the functional integrity of the enzyme. The study defines the CORD in molecular terms, at a most basic level identifies a region that is critical in its dimer formation, and, thus, discloses a single unifying mechanistic theme underlying the complex pathology of the disease.Phototransduction is a biochemical process by which the vertebrate rods and cones generate electrical signals in response to captured photons (reviewed in refs 1 and 2). This process occurs in the rod (or cone) outer segments (ROS). 1The photon induces a decline in the level of cyclic GMP and closure of the cyclic GMP-gated cation channels. This results in a drop of intracellular Ca 2+ from ∼500 nM in darkadapted photoreceptor cell to below 100 nM after illumination. This drop activates ROS guanylate cyc...

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Section: Discussionmentioning

confidence: 99%

Section: Hek293 and Cos Cells Expression Systems Are Comparable It Wmentioning

confidence: 99%

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Impairment of the Rod Outer Segment Membrane Guanylate Cyclase Dimerization in A Cone−Rod Dystrophy Results in Defective Calcium Signaling

et al. 2000

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“…7B) was modeled on the basis of the crystal structure of Ca 2ϩ -bound neurocalcin (1BJF), which is the closest available structure of a Ca 2ϩ -bound NCS protein dimer that has highest sequence identity to VILIP-1. Ca 2ϩ -bound neurocalcin forms a dimer in solution (54), and the crystal structure of the Ca 2ϩ -bound dimer (26) specifies intermolecular contacts primarily between residues in the N-terminal domain (EF1 and EF2) and exposed residues in EF3. Our chimera analysis above on VILIP-1 precludes any intermolecular dimer contacts involving residues in EF1, EF2, and EF3 (i.e.…”

Section: Two-dimensionalmentioning

confidence: 99%

Structural Analysis of Mg2+ and Ca2+ Binding, Myristoylation, and Dimerization of the Neuronal Calcium Sensor and Visinin-like Protein 1 (VILIP-1)

Pan

Braunewell

et al. 2011

Journal of Biological Chemistry

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2؉ and myristoylation. The dimerization site is composed of residues in EF4 and the loop region between EF3 and EF4, confirmed by mutagenesis. We present the structure of the VILIP-1 dimer and a Ca 2؉ -myristoyl switch to provide structural insights into Ca 2؉ -induced trafficking of nicotinic acetylcholine receptors. Visinin-like protein 1 (VILIP-1)2 is a neuronal Ca 2ϩ sensor (NCS) protein belonging to the calmodulin superfamily of calcium sensor proteins (1-4). VILIP-1 is expressed throughout the brain with high expression levels in the rat hippocampus (5, 6), where it may play a role in regulating synaptic plasticity relevant for learning and memory (7,8). VILIP-1 regulates several neuronal signaling pathways implicated in synaptic plasticity, such as cyclic nucleotide cascades (9 -12) and nicotinergic signaling (13). Moreover, VILIP-1 binds to the ␣-subunit of the ␣ 4 ␤ 2 nicotinic acetylcholine receptor (nAChR) and promotes surface expression and trafficking of ␣ 4 ␤ 2 nAChR in oocytes (13) and hippocampal neurons (14). VILIP-1 has been implicated in the modulation of neuronal excitability by influencing ␣ 4 ␤ 2 nAChR signaling in hippocampal neurons (14 -16). VILIP-1 has also been implicated in the pathology of CNS diseases (17), including Alzheimer's disease (18, 19) and schizophrenia. Indeed, VILIP-1 expression shows cell-specific changes in the brains of schizophrenics and in animal models of the disease (16,20,21). Thus, VILIP-1 appears to be an important Ca 2ϩ sensor for controlling neuronal excitability by modulating nicotinergic neurotransmission important for synaptic plasticity and disease processes (17,22).VILIP-1 belongs to the NCS family of Ca 2ϩ -myristoyl switch proteins (Fig. 1). The three-dimensional structures are known for NCS-1 (23), recoverin (24, 25), and neurocalcin (26). The common structural features of NCS proteins are an ϳ200-residue chain containing four EF-hand motifs (EF1, EF2, EF3, and EF4), the sequence CPXG in the first EF-hand that eliminates its capacity to bind Ca 2ϩ and an N-terminal myristoylation consensus sequence. The binding of Ca 2ϩ to NCS proteins (e.g. NCS-1 (27), recoverin (28), and neurocalcin (29)) induces their binding to cellular membranes (29 -31). The N-terminal myristoyl group has been shown to be sequestered structurally inside Ca 2ϩ -free recoverin (32, 33), whereas the binding of two Ca 2ϩ to recoverin leads to the extrusion of the covalently attached myristoyl group (24). The Ca 2ϩ -induced exposure of the myristoyl group, termed Ca 2ϩ -myristoyl switch, enables recoverin and related NCS proteins to bind membranes only at high Ca 2ϩ . In this study, we report on the structural analysis of Ca 2ϩ and Mg 2ϩ binding to VILIP-1 to characterize the structural mechanism of the Ca 2ϩ -myristoyl switch and determine its dimeric structure. We show that VILIP-1 binds functionally to Mg 2ϩ at EF3 and binds cooperatively to Ca 2ϩ at EF2 and EF3. VILIP-1 sequesters its N-terminal myristoyl group inside the apo-protein core and exhibits Ca 2ϩ -induced extrusion o...

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“…The dimerization and activation of GC-E are abolished in a GCAPdepleted membrane preparation of the retina, and added recombinant constitutively active mutants of GCAP-1 and GCAP-2 cause dimerization and high activity of GC-E even at high Ca2+ concentrations (> 1 tcM) [145]. GCAP-2 dimerization caused by decrease of the intracellular Ca2+ concentration is also reported, and it is suggested that the dimerization of GCAPs might be a mechanism for the GC-E and GC-F activation [145,146].…”

Section: Regulation Of Guanylyl Cyclases By Associated Proteinsmentioning

confidence: 99%

The Regulation and Physiological Roles of the Guanylyl Cyclase Receptors.

2001

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Dimerization of Guanylyl Cyclase-activating Protein and a Mechanism of Photoreceptor Guanylyl Cyclase Activation

Cited by 83 publications

References 41 publications

Impairment of the Rod Outer Segment Membrane Guanylate Cyclase Dimerization in A Cone−Rod Dystrophy Results in Defective Calcium Signaling

Impairment of the Rod Outer Segment Membrane Guanylate Cyclase Dimerization in A Cone−Rod Dystrophy Results in Defective Calcium Signaling

Structural Analysis of Mg2+ and Ca2+ Binding, Myristoylation, and Dimerization of the Neuronal Calcium Sensor and Visinin-like Protein 1 (VILIP-1)

The Regulation and Physiological Roles of the Guanylyl Cyclase Receptors.

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