cd04043

C2 domain in Munc13 (mammalian uncoordinated) proteins; fungal group

CDD entry
Member databaseCDD
CDD typedomain
Short nameC2_Munc13_fungal
SetC2

Description

C2-like domains are thought to be involved in phospholipid binding in a Ca2+ independent manner in both Unc13 and Munc13. Caenorabditis elegans Unc13 has a central domain with sequence similarity to PKC, which includes C1 and C2-related domains. Unc13 binds phorbol esters and DAG with high affinity in a phospholipid manner. Mutations in Unc13 results in abnormal neuronal connections and impairment in cholinergic neurotransmission in the nematode. Munc13 is the mammalian homolog which are expressed in the brain. There are 3 isoforms (Munc13-1, -2, -3) and are thought to play a role in neurotransmitter release and are hypothesized to be high-affinity receptors for phorbol esters. Unc13 and Munc13 contain both C1 and C2 domains. There are two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. Munc13 interacts with syntaxin, synaptobrevin, and synaptotagmin suggesting a role for these as scaffolding proteins. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-II topology.
[8, 5, 1, 4, 7, 6, 2, 3]

References

1.Extending the C2 domain family: C2s in PKCs delta, epsilon, eta, theta, phospholipases, GAPs, and perforin. Ponting CP, Parker PJ. Protein Sci. 5, 162-6, (1996). View articlePMID: 8771209

2.Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Brose N, Petrenko AG, Sudhof TC, Jahn R. Science 256, 1021-5, (1992). View articlePMID: 1589771

3.Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C. Perin MS, Fried VA, Mignery GA, Jahn R, Sudhof TC. Nature 345, 260-3, (1990). View articlePMID: 2333096

4.Bipartite Ca2+-binding motif in C2 domains of synaptotagmin and protein kinase C. Shao X, Davletov BA, Sutton RB, Sudhof TC, Rizo J. Science 273, 248-51, (1996). View articlePMID: 8662510

5.The C2 domain calcium-binding motif: structural and functional diversity. Nalefski EA, Falke JJ. Protein Sci. 5, 2375-90, (1996). View articlePMID: 8976547

6.Structure of the first C2 domain of synaptotagmin I: a novel Ca2+/phospholipid-binding fold. Sutton RB, Davletov BA, Berghuis AM, Sudhof TC, Sprang SR. Cell 80, 929-38, (1995). View articlePMID: 7697723

7.Ca(2+)-dependent and -independent activities of neural and non-neural synaptotagmins. Li C, Ullrich B, Zhang JZ, Anderson RG, Brose N, Sudhof TC. Nature 375, 594-9, (1995). View articlePMID: 7791877

8.C2-domains, structure and function of a universal Ca2+-binding domain. Rizo J, Sudhof TC. J. Biol. Chem. 273, 15879-82, (1998). View articlePMID: 9632630

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