Metal insertion into the molybdenum cofactor: product–substrate channelling demonstrates the functional origin of domain fusion in gephyrin

Belaidi, Abdel Ali; Schwarz, Günter

doi:10.1042/bj20121078

Cited by 51 publications

(42 citation statements)

References 48 publications

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“…Furthermore, gephyrin is also crucial for Moco synthesis, as it catalyzes the 2-step metal insertion reaction (44). Consistent with this, Gphn-KO mice exhibit a neurological phenotype more severe than that of MoCD; indeed, homozygous-KO mice die within the first day of life (45).…”

Section: Discussionsupporting

confidence: 49%

S-sulfocysteine/NMDA receptor–dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency

Kumar¹,

Dejanovic²,

Hetsch³

et al. 2017

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 49%

S-sulfocysteine/NMDA receptor–dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency

Kumar¹,

Dejanovic²,

Hetsch³

et al. 2017

Journal of Clinical Investigation

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“…The C domain links the G and E domains and harbours numerous sites for post-translational modification and interaction with proteins regulating synapse formation and function 2 . Gephyrin more efficiently synthesizes Moco than do the isolated G and E domains 162 , indicating an evolutionary advantage for protein fusion and structural rearrangements that gave rise to vertebrate gephyrin and allowed novel functions to emerge from the fused protein. In particular, gephyrin possesses a non-conserved surface-exposed loop in the E domain, which regulates its postsynaptic clustering in an all-or-none fashion 22 .…”

Section: Box 1: Gephyrin Structurementioning

confidence: 99%

Gephyrin: a master regulator of neuronal function?

2014

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The neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligandgated chloride channels-namely, type A GABA (GABA(A)) and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that postsynaptic gephyrin clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, post-translational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules. Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission. Shiva Tyagarajan graduated as a molecular virologist at the Pennsylvania State University (USA) and later trained as a neurobiologist during his post-doctoral studies at the University of Zurich. He is currently a group leader and the research focus of his group is to elucidate molecular and cellular mechanisms that couple transcriptional and post-transcriptional programs to regulate GABAergic synaptic plasticity. 3 AbstractThe neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligand-gated Cl  channels, namely the GABA A and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that gephyrin postsynaptic clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, posttranslational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses, by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules.Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission.On-line summary  Gephyrin is a multi-functional protein, responsible for Moco biosynthesis in all organisms, and for postsynaptic clustering of glycine receptors and GABAA receptors in vertebrate CNS  Gephyrin forms a protein scaffold by self-assembly from trimeric complexes, which interacts with numerous, structurally different proteins, in order to form a high ordered signalling complex in glycinergic and GABAergic synapses  Gephyrin function as a scaffolding protein is regulated by alternate mRNA splicing and by multiple post-transcriptional and posttranslational modifications, which only begin to be understood.  Regulation of gephyrin scaffold by multiple signallin...

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“…Both domains were fused at least two times during evolution, resulting in two-domain proteins with different orientations of the G-and E-domains: plants have the E-domain at the N terminus of the protein, and mammals and fungi have the G-domain at the N terminus (2,27). These evolutionarily distinct events point to a high pressure and a functional benefit of having the adenylation function and the metal insertion function coupled into one protein, where the fragile intermediate MPT-AMP is channeled from the G-domain to the E-domain (49).…”

Section: Product-substrate Channeling In Moco Biosynthesismentioning

confidence: 99%

The Molybdenum Cofactor

Mendel

2013

Journal of Biological Chemistry

244

181

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The transition element molybdenum needs to be complexed by a special cofactor to gain catalytic activity. Molybdenum is bound to a unique pterin, thus forming the molybdenum cofactor (Moco), which, in different variants, is the active compound at the catalytic site of all molybdenum-containing enzymes in nature, except bacterial molybdenum nitrogenase. The biosynthesis of Moco involves the complex interaction of six proteins and is a process of four steps, which also require iron, ATP, and copper. After its synthesis, Moco is distributed, involving Mocobinding proteins. A deficiency in the biosynthesis of Moco has lethal consequences for the respective organisms.The transition element molybdenum is an essential micronutrient for microorganisms, plants, and animals (1). Surprisingly, molybdenum itself is catalytically inactive in biological systems until it is complexed by a special scaffold (2). One type of scaffold is the ubiquitous pterin-based molybdenum cofactor (Moco), 2 which, in different variants, forms part of the active centers of all molybdenum enzymes in living organisms, except one. This exception is bacterial nitrogenase, which harbors the other type of cofactor, namely the Fe-S cluster-based FeMo cofactor, which is found only once in nature (for details, compare the minireview of Hu and Ribbe (62) in this thematic series). Molybdenum belongs to the group of trace elements, i.e. the organism needs it only in minute amounts; however, unavailability of molybdenum is lethal for the organism. Molybdenum is very abundant in the oceans in the form of the molybdate anion (3). In soils, the molybdate anion is the only form of molybdenum that is available for bacteria, plants, and fungi. More than 50 enzymes are known to be molybdenumdependent. The vast majority of them are found in bacteria, whereas only seven have been identified in eukaryotes (4, 5). It is somewhat surprising that not all organisms need molybdenum. The commonly used eukaryotic model organism yeast plays no role in molybdenum research, as Saccharomyces cerevisiae does not contain either molybdenum enzymes or the Moco biosynthesis pathway. Also Schizosaccharomyces pombe does not use molybdenum, whereas Pichia pastoris needs molybdenum. Genome-wide database analyses revealed a significant number of bacteria and unicellular eukaryotes that do not need molybdenum, whereas all multicellular eukaryotes are dependent on molybdenum (6). In addition, mainly anaerobic archaea and some bacteria are molybdenum-independent, but they require tungsten for their growth (7). In the periodic table of elements, tungsten lies directly below molybdenum and features chemical properties similar to molybdenum.Molybdenum metabolism is tightly connected to Fe-S cluster synthesis in that some of the molybdenum enzymes and Moco biosynthesis itself depend on Fe-S enzymes and on a mitochondrial transporter that is known to be crucial for the maturation of cytosolic Fe-S proteins. Moreover, Moco biosynthesis recruits mechanisms previously known from Fe-S cluster synthe...

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Metal insertion into the molybdenum cofactor: product–substrate channelling demonstrates the functional origin of domain fusion in gephyrin

Cited by 51 publications

References 48 publications

S-sulfocysteine/NMDA receptor–dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency

S-sulfocysteine/NMDA receptor–dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency

Gephyrin: a master regulator of neuronal function?

The Molybdenum Cofactor

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