Doc2: A Novel Brain Protein Having Two Repeated C2-like Domains

Orita, Satoshi; Sasaki, Takuya; Naito, Akira; Komuro, Ryutaro; Ohtsuka, Toshikazu; Maeda, Mineko; Suzuki, Harukazu; Igarashi, Hisanaga; Takai, Yoshimi

doi:10.1006/bbrc.1995.1062

Cited by 124 publications

(110 citation statements)

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“…It consists of a short amino-terminal intravesicular domain, a single transmembrane region and a larger cytoplasmic region [4]. The latter contains two internal repeats that are similar to the C2 domains found in several isoforms of protein kinase C, some phospholipases, rabphilin 3A, GTPase activating protein, brain protein Doc2 and the C. elegans protein unc-13 [8][9][10][11][12][13][14]. C2 domains confer Ca 2+-dependent phospholipid binding to at least some of these proteins.…”

Section: Introductionmentioning

confidence: 99%

Synaptotagmin V: a novel synaptotagmin isoform expressed in rat brain

Craxton

Goedert

1995

FEBS Letters

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Regulated Ca2+-dependent release of transmitters from synaptic vesicles is an important characteristic of chemical neurotransmission. Synaptotagmins are abundant synaptic vesicle transmembrane proteins that probably function as Ca 2+ sensors. Molecular cloning has identified four different synaptotagmin isoforms in mammals. We report here the cloning and sequencing of a novel isoform of 386 amino acids. Synaptotagmin V is 54% identical in sequence to synaptotagmin I and possesses all the domains that characterise this multigene family. It is expressed at high levels in rat brain, but not in spinal cord or a number of peripheral non-neuronal tissues.

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Section: Introductionmentioning

confidence: 99%

Synaptotagmin V: a novel synaptotagmin isoform expressed in rat brain

Craxton

Goedert

1995

FEBS Letters

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“…The Doc2 distribution was, however, similar to that of PC12 dense-core granules, which are indicated by the presence of secretogranin II, a protein present in dense-core granule contents. The distribution of Doc2 differed from that of the endosomal markers Rab5 (distributed over fractions [1][2][3][4][5][6][7][8] and Rab7 (fractions 5 and 6), but was again very similar to that of the mitochondrial protein GDH ( Figure 4A). In addition, the distribution of Doc2 was not identical with that of its proposed binding partner munc-18, which showed a peak in fractions 6 and 7 and had a more widespread presence in lighter fractions compared with Doc2.…”

Section: Resultsmentioning

confidence: 87%

“…Doc2 has been described as a synaptic vesicle protein [6,8]. Previous work has detected Doc2 in a synaptic vesicle fraction from rat brain, but without the marked enrichment during purification expected for a bona fide synaptic vesicle protein [6,8].…”

Section: Discussionmentioning

confidence: 98%

“…These include the synaptotagmins [3], rabphilin [4], Rim [5] and Doc2 [6], all of which are expressed at high levels in neuronal tissues. Doc2 contains two C2 domains, which are likely to allow its Ca# + -dependent binding to phospholipids [7], and it has been implicated in regulated exocytosis as a result of its ability to bind munc-18 (nsec-1) [8] and munc-13 [9].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, overexpression of Doc2 increased the release of co-transfected growth hormone (as a marker of secretory granule contents) from neuroendocrine PC12 cells, and cotransfection with N-or C-terminal fragments of Doc2 was inhibitory [12]. Doc2 is present, but not highly enriched, in synaptic vesicle fractions [6,8], and so it is unclear whether or not it is a bona fide secretory vesicle protein.…”

Section: Introductionmentioning

confidence: 99%

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Doc2 is not associated with known regulated exocytotic or endosomal compartments in adrenal chromaffin cells

Charvin

Williams

Burgoyne

1999

Biochemical Journal

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Doc2 is a C2-domain-containing protein that is highly expressed in the nervous system and has a constitutively expressed isoform. It has been implicated as a potential Ca2+ sensor in regulated exocytosis, and has been suggested to be associated with synaptic vesicles. To examine whether Doc2 is associated with synaptic-like microvesicles (SLMVs) or dense-core granules in neuroendocrine cells, we examined the distribution of Doc2 in subcellular fractionation of chromaffin cells of the adrenal medulla and in PC12 cells. Doc2 did not co-distribute with SLMVs from either cell type, but did appear to co-distribute with dense-core granules from PC12 cells. In contrast, it was not associated with the dense-core granules during subcellular fractionation of the adrenal medulla, and nor did it appear to be associated with endosomes, cis-Golgi or the trans-Golgi network. In contrast, Doc2 co-distributed under all conditions with a mitochondrial marker. We conclude that Doc2 is not a general component of regulated secretory vesicles, but may instead be associated with mitochondria.

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C 2‐Domain Proteins Involved in Membrane Traffic

Rizo

2004

Handbook of Metalloproteins

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C 2 ‐domains are the second‐most abundant Ca 2+ ‐binding modules in nature. Their most common activity is Ca 2+ ‐dependent phospholipid binding, but other types of interactions have been observed for these versatile protein modules. A variety of proteins involved in membrane traffic contain multiple C 2 ‐domains, which often appear as two tandem C 2 ‐domains as in the case of synaptotagmins and rabphilin. The structures of the C 2 ‐domains of these proteins consist of a conserved β‐sandwich, formed by two four‐stranded β‐sheets, with variable loops at the top and the bottom that sometimes contain α‐helices. Multiple Ca 2+ ‐ions bind in a tight cluster at the top loops, usually without inducing substantial conformational changes. Instead, electrostatic changes caused by Ca 2+ binding induce the Ca 2+ ‐dependent interactions of C 2 ‐domains, which can also be aided by hydrophobic interactions and partial coordination of Ca 2+ by the target molecules. Extensive analysis of the structure and Ca 2+ ‐binding properties of the two synaptotagmin 1 C 2 ‐domains has helped design genetic experiments that have strongly supported the notion that this protein acts as the major Ca 2+ sensor in neurotransmitter release. These studies have also suggested that Ca 2+ ‐dependent phospholipid binding underlies the function of synaptotagmin 1 in triggering release.

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Doc2: A Novel Brain Protein Having Two Repeated C2-like Domains

Cited by 124 publications

References 0 publications

Synaptotagmin V: a novel synaptotagmin isoform expressed in rat brain

Synaptotagmin V: a novel synaptotagmin isoform expressed in rat brain

Doc2 is not associated with known regulated exocytotic or endosomal compartments in adrenal chromaffin cells

C 2‐Domain Proteins Involved in Membrane Traffic

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