Splice-specific Functions of Gephyrin in Molybdenum Cofactor Biosynthesis

Smolinsky, Birthe; Eichler, Sabrina A.; Buchmeier, Sabine; Meier, Jochen C.; Schwarz, Günter

doi:10.1074/jbc.m800985200

Cited by 53 publications

(67 citation statements)

References 47 publications

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“…The majority of modifications reside in the C domain, pointing toward its crucial contribution in controlling gephyrin folding and clustering. Among eight of the most frequently found gephyrin splice variants, we found no impact on gephyrin metabolic function for all C domain splice variants, whereas the insertion of the G2 cassette (previously named C5) (26), rendered dimer formation of the G-domain (28).…”

mentioning

confidence: 85%

“…Given the known domain oligomerizations, it remained a challenge for more than a decade to prepare highly pure holo-gephyrin, which would allow its crystallization and structure determination. Knowing that the concerted interaction of all three domains is required for proper neuronal function of gephyrin (18,19,28), it becomes critical to disclose the molecular interplay between all three domains on the atomic level.…”

Section: Discussionmentioning

confidence: 99%

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Splice-specific Glycine Receptor Binding, Folding, and Phosphorylation of the Scaffolding Protein Gephyrin

Herweg

Schwarz

2012

Journal of Biological Chemistry

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Background: Gephyrin is a postsynaptic scaffolding protein at inhibitory synapses and undergoes alternative splicing. Results: Gephyrin splice variants expressed in insect cells were purified as stable hexamers and high-oligomers. Splice-specific folding and stability, glycine receptor ␤-loop binding, and phosphorylation of gephyrin were found. Conclusion: Splicing and phosphorylation controls gephyrin clustering via conformational changes within the C domain. Significance: Novel regulatory circuits controlling gephyrin clustering.

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confidence: 85%

Section: Discussionmentioning

confidence: 99%

Splice-specific Glycine Receptor Binding, Folding, and Phosphorylation of the Scaffolding Protein Gephyrin

Herweg

Schwarz

2012

Journal of Biological Chemistry

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“…The gephyrin transcript is subject to extensive alternative splicing 10,19,20 in all three domains. Each domain contains at least three variable expression cassettes, providing a regulatory mechanism through which the signaling properties of specific synapses may be altered.…”

Section: Introductionmentioning

confidence: 99%

Gephyrin: a central GABAergic synapse organizer

2015

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Gephyrin is a central element that anchors, clusters and stabilizes glycine and γ-aminobutyric acid type A receptors at inhibitory synapses of the mammalian brain. It self-assembles into a hexagonal lattice and interacts with various inhibitory synaptic proteins. Intriguingly, the clustering of gephyrin, which is regulated by multiple posttranslational modifications, is critical for inhibitory synapse formation and function. In this review, we summarize the basic properties of gephyrin and describe recent findings regarding its roles in inhibitory synapse formation, function and plasticity. We will also discuss the implications for the pathophysiology of brain disorders and raise the remaining open questions in this field.

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“…However, there are Wrst indications that the insertion of certain cassettes may interfere with the formation of higher order GlyR structures (Saiyed et al 2007) or the postsynaptic stabilization of GlyRs in cultures spinal cord neurons (Meier and Grantyn 2004). Moreover, gephyrin containing the C5 cassette has been shown to be unable to catalyze the Wnal step in molybdenum cofactor (see below) biosynthesis in vitro (Smolinsky et al 2008), indicating that alternative splicing may change diVerent properties of gephyrin in a given cellular context. Unexpectedly, Northern blots revealed, that gephyrin mRNAs are expressed in many organs except those of the lymphatic system (Prior et al 1992).…”

Section: Splice Variants Expression and Distributionmentioning

confidence: 99%

“…4). Indeed, molybdopterin (a precursor of moco) binding of gephyrin and its orthologs was demonstrated (Schwarz and Mendel 2006;Smolinsky et al 2008) and its role in the moco biosynthetic pathway is well established (Reiss et al 2001). Curiously, the G-domain of rat gephyrin could functionally replace the corresponding protein of Arabidopsis mutants lacking the cnx1 protein (Stallmeyer et al 1999) and conversely, transgenic expression of cnx1 in gephyrin-deWcient mice could partially restore the activity of moco-dependent enzymes (Grosskreutz et al 2003).…”

Section: Homologous Proteinsmentioning

confidence: 99%

Molecular architecture of glycinergic synapses

Dresbach

Nawrotzki

Kremer

et al. 2008

Histochem Cell Biol

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Synapses can be considered chemical machines, which are optimized for fast and repeated exocytosis of neurotransmitters from presynaptic nerve terminals and the reliable electrical or chemical transduction of neurotransmitter binding to the appropriate receptors in the postsynaptic membrane. Therefore, synapses share a common repertoire of proteins like, e.g., the release machinery and certain cell adhesion molecules. This basic repertoire must be extended in order to generate speciWcity of neurotransmission and allow plastic changes, which are considered the basis of developmental and/or learning processes. Here, we focus on these complementary molecules located in the presynaptic terminal and postsynaptic membrane specializations of glycinergic synapses. Moreover, as speciWcity of neurotransmission in this system is established by the speciWc binding of the neurotransmitter to its receptor, we review the molecular properties of glycine receptor subunits and their assembly into functional glycine receptors with diVerent functional characteristics. The past years have revealed that the molecular machinery underlying inhibitory and especially glycinergic postsynaptic membrane specializations is more complex and dynamic than previously anticipated from morphological studies. The emerging features include structural components as well as signaling modules, which could confer the plasticity required for the proper function of distinct motor and sensory functions.

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Splice-specific Functions of Gephyrin in Molybdenum Cofactor Biosynthesis

Abstract: Gephyrin is a multifunctional protein involved in the clustering

Cited by 53 publications

References 47 publications

Splice-specific Glycine Receptor Binding, Folding, and Phosphorylation of the Scaffolding Protein Gephyrin

Splice-specific Glycine Receptor Binding, Folding, and Phosphorylation of the Scaffolding Protein Gephyrin

Gephyrin: a central GABAergic synapse organizer

Molecular architecture of glycinergic synapses

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