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PubMed2005

MxA, a member of the dynamin superfamily, interacts with the ankyrin-like repeat domain of TRPC.

Mammalian transient receptor potential canonical channels have been proposed as the molecular entities associated with calcium entry activity in nonexcitable cells. Amino acid sequence analyses of TRPCs revealed the presence of ankyrin-like repeat domains, one of the most common protein-protein interaction motifs. Using a yeast two-hybrid interaction assay, we found that the second ankyrin-like repeat domain of TRPC6 interacted with MxA, a member of the dynamin superfamily. Using a GST pull-down and co-immunoprecipitation assay, we showed that MxA interacted with TRPC1, -3, -4, -5, -6, and -7. Overexpression of MxA in HEK293T cells slightly increased endogenous calcium entry subsequent to stimulation of G(q) protein-coupled receptors or store depletion by thapsigargin. Co-expression of MxA with TRPC6 enhanced agonist-induced or OAG-induced calcium entry activity. GTP binding-defective MxA mutants had only a minor potentiating effect on OAG-induced TRPC6 activity. However, a MxA mutant that could bind GTP but that lacked GTPase activity produced the same effect as MxA on OAG-induced TRPC6 activity. These results indicated that MxA interacted specifically with the second ankyrin-like repeat domain of TRPCs and suggested that monomeric MxA regulated the activity of TRPC6 by a mechanism requiring GTP binding. Additional results showed that an increase in the endogenous expression of MxA, induced by a treatment with interferon alpha, regulated the activity of TRPC6. The study clearly identified MxA as a new regulatory protein involved in Ca2+ signaling.

Amino Acid Motifs↗
PubMed1999

The yeast dynamin-like protein, Mgm1p, functions on the mitochondrial outer membrane to mediate mitochondrial inheritance.

The mdm17 mutation causes temperature-dependent defects in mitochondrial inheritance, mitochondrial morphology, and the maintenance of mitochondrial DNA in the yeast Saccharomyces cerevisiae. Defects in mitochondrial transmission to daughter buds and changes in mitochondrial morphology were apparent within 30 min after shifting cells to 37 degrees C, while loss of the mitochondrial genome occurred after 4-24 h at the elevated temperature. The mdm17 lesion mapped to MGM1, a gene encoding a dynamin-like GTPase previously implicated in mitochondrial genome maintenance, and the cloned MGM1 gene complements all of the mdm17 mutant phenotypes. Cells with an mgm1-null mutation displayed aberrant mitochondrial inheritance and morphology. A version of mgm1 mutated in a conserved residue in the putative GTP-binding site was unable to complement any of the mutant defects. It also caused aberrant mitochondrial distribution and morphology when expressed at high levels in cells that also contained a wild-type copy of the gene. Mgm1p was localized to the mitochondrial outer membrane and fractionated as a component of a high molecular weight complex. These results indicate that Mgm1p is a mitochondrial inheritance and morphology component that functions on the mitochondrial surface.

Alleles↗
PubMed2003

Mgm1p, a dynamin-related GTPase, is essential for fusion of the mitochondrial outer membrane.

In Saccharomyces cerevisiae, mitochondrial fusion requires at least two outer membrane proteins, Fzo1p and Ugo1p. We provide direct evidence that the dynamin-related Mgm1 protein is also required for mitochondrial fusion. Like fzo1 and ugo1 mutants, cells disrupted for the MGM1 gene contain numerous mitochondrial fragments instead of the few long, tubular organelles seen in wild-type cells. Fragmentation of mitochondria in mgm1 mutants is rescued by disrupting DNM1, a gene required for mitochondrial division. In zygotes formed by mating mgm1 mutants, mitochondria do not fuse and mix their contents. Introducing mutations in the GTPase domain of Mgm1p completely block mitochondrial fusion. Furthermore, we show that mgm1 mutants fail to fuse both their mitochondrial outer and inner membranes. Electron microscopy demonstrates that although mgm1 mutants display aberrant mitochondrial inner membrane cristae, mgm1 dnm1 double mutants restore normal inner membrane structures. However, mgm1 dnm1 mutants remain defective in mitochondrial fusion, indicating that mitochondrial fusion requires Mgm1p regardless of the morphology of mitochondria. Finally, we find that Mgm1p, Fzo1p, and Ugo1p physically interact in the mitochondrial outer membrane. Our results raise the possibility that Mgm1p regulates fusion of the mitochondrial outer membrane through its interactions with Fzo1p and Ugo1p.

DNA, Mitochondrial↗
PubMed2000

Synthetic genetic interactions with temperature-sensitive clathrin in Saccharomyces cerevisiae. Roles for synaptojanin-like Inp53p and dynamin-related Vps1p in clathrin-dependent protein sorting at the trans-Golgi network.

Clathrin is involved in selective protein transport at the Golgi apparatus and the plasma membrane. To further understand the molecular mechanisms underlying clathrin-mediated protein transport pathways, we initiated a genetic screen for mutations that display synthetic growth defects when combined with a temperature-sensitive allele of the clathrin heavy chain gene (chc1-521) in Saccharomyces cerevisiae. Mutations, when present in cells with wild-type clathrin, were analyzed for effects on mating pheromone alpha-factor precursor maturation and sorting of the vacuolar protein carboxypeptidase Y as measures of protein sorting at the yeast trans-Golgi network (TGN) compartment. By these criteria, two classes of mutants were obtained, those with and those without defects in protein sorting at the TGN. One mutant with unaltered protein sorting at the TGN contains a mutation in PTC1, a type 2c serine/threonine phosphatase with widespread influences. The collection of mutants displaying TGN sorting defects includes members with mutations in previously identified vacuolar protein sorting genes (VPS), including the dynamin family member VPS1. Striking genetic interactions were observed by combining temperature-sensitive alleles of CHC1 and VPS1, supporting the model that Vps1p is involved in clathrin-mediated vesicle formation at the TGN. Also in the spectrum of mutants with TGN sorting defects are isolates with mutations in the following: RIC1, encoding a product originally proposed to participate in ribosome biogenesis; LUV1, encoding a product potentially involved in vacuole and microtubule organization; and INP53, encoding a synaptojanin-like inositol polyphosphate 5-phosphatase. Disruption of INP53, but not the related INP51 and INP52 genes, resulted in alpha-factor maturation defects and exacerbated alpha-factor maturation defects when combined with chc1-521. Our findings implicate a wide variety of proteins in clathrin-dependent processes and provide evidence for the selective involvement of Inp53p in clathrin-mediated protein sorting at the TGN.

Base Sequence↗
PubMed2006

Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease.

The apolipoprotein E (APOE) gene has been consistently shown to be a major genetic risk factor; however, all cases of Alzheimer's disease (AD) cannot be attributed to the epsilon4 variant of APOE, because about half of AD patients have the APOE-epsilon3*3 genotype. To identify an additional genetic risk factor(s), we performed large-scale single nucleotide polymorphism (SNP)-based association analysis of 1526 late-onset AD patients and 1666 control subjects in a Japanese population. We prepared two independent sets consisting of exploratory and validation samples, respectively, with only the APOE-epsilon3*3 genotype, and first carried out genotyping for the exploratory set with 1206 SNPs in the region between 60 and 107 Mb on chromosome 10q that is implicated by linkage studies as containing an AD susceptibility locus. Thirty-five SNPs that showed significant values (P<0.01) were followed-up to detect any association with the validation samples. Finally, six SNPs exhibited replicated significant associations (P=0.000035-0.00048) on meta-analysis of both sets. These SNPs were clustered in a locus spanning 220 kb at genomic position 101 Mb, and three of the six SNPs were located in the dynamin-binding protein (DNMBP) gene. Quantitative real-time RT-PCR analysis demonstrated that neuropathologically confirmed AD brains exhibit a significant reduction of DNMBP mRNA compared with age-matched ones (P<0.0169). Thus, we confirmed the association of DNMBP with AD individuals with the APOE-epsilon3*3 genotype or lacking the epsilon4 allele, and DNMBP may be one of the susceptibility genes for AD.

Aged↗
PubMed2004

Arabidopsis dynamin-like protein 2a (ADL2a), like ADL2b, is involved in plant mitochondrial division.

The Arabidopsis genome has two similar dynamin-like proteins, ADL2a and ADL2b (76.7% identity). ADL2a is reported to be localized in chloroplasts [Kang et al. (1998) Plant Mol. Biol. 38: 437], while ADL2b functions in mitochondrial division [Arimura and Tsutsumi (2002) PROC: Natl. Acad. Sci. USA 99: 5727]. Using GFP fusion proteins, we observed both ADL2a and ADL2b in portions of mitochondria but not in chloroplasts. Furthermore, cells transformed with ADL2a and ADL2b with a defective GTPase domain had normal chloroplasts but elongated mitochondria. These results imply that both ADL2b and ADL2a are involved in the division of plant mitochondria.

Amino Acid Sequence↗
PubMed2006

A mutation in the GTP hydrolysis site of Arabidopsis dynamin-related protein 1E confers enhanced cell death in response to powdery mildew infection.

We screened for mutants of Arabidopsis thaliana that displayed enhanced disease resistance to the powdery mildew pathogen Erysiphe cichoracearum and identified the edr3 mutant, which formed large gray lesions upon infection with E. cichoracearum and supported very little sporulation. The edr3-mediated disease resistance and cell death phenotypes were dependent on salicylic acid signaling, but independent of ethylene and jasmonic acid signaling. In addition, edr3 plants displayed enhanced susceptibility to the necrotrophic fungal pathogen Botrytis cinerea, but showed normal responses to virulent and avirulent strains of Pseudomonas syringae pv. tomato. The EDR3 gene was isolated by positional cloning and found to encode Arabidopsis dynamin-related protein 1E (DRP1E). The edr3 mutation caused an amino acid substitution in the GTPase domain of DRP1E (proline 77 to leucine) that is predicted to block GTP hydrolysis, but not GTP binding. A T-DNA insertion allele in DRP1E did not cause powdery mildew-induced lesions, suggesting that this phenotype is caused by DRP1E being locked in the GTP-bound state, rather than by a loss of DRP1E activity. Analysis of DRP1E-green fluorescent protein fusion proteins revealed that DRP1E is at least partially localized to mitochondria. These observations suggest a mechanistic link between salicylic acid signaling, mitochondria and programmed cell death in plants.

Aging↗
PubMed2004

Patched controls the Hedgehog gradient by endocytosis in a dynamin-dependent manner, but this internalization does not play a major role in signal transduction.

The Hedgehog (Hh) morphogenetic gradient controls multiple developmental patterning events in Drosophila and vertebrates. Patched (Ptc), the Hh receptor, restrains both Hh spreading and Hh signaling. We report how endocytosis regulates the concentration and activity of Hh in the wing imaginal disc. Our studies show that Ptc limits the Hh gradient by internalizing Hh through endosomes in a dynamin-dependent manner, and that both Hh and Ptc are targeted to lysosomal degradation. We also found that the ptc(14) mutant does not block Hh spreading, as it has a failure in endocytosis. However, this mutant protein is able to control the expression of Hh target genes as the wild-type protein, indicating that the internalization mediated by Ptc is not required for signal transduction. In addition, we noted that both in this mutant and in those not producing Ptc protein, Hh still occurred in the endocytic vesicles of Hh-receiving cells, suggesting the existence of a second, Ptc-independent, mechanism of Hh internalization.

Animals↗
PubMed2006

Dynamin-related proteins Vps1p and Dnm1p control peroxisome abundance in Saccharomyces cerevisiae.

Saccharomyces cerevisiae contains three dynamin-related-proteins, Vps1p, Dnm1p and Mgm1p. Previous data from glucose-grown VPS1 and DNM1 null mutants suggested that Vps1p, but not Dnm1p, plays a role in regulating peroxisome abundance. Here we show that deletion of DNM1 also results in reduction of peroxisome numbers. This was not observed in glucose-grown dnm1 cells, but was evident in cells grown in the presence of oleate. Similar observations were made in cells lacking Fis1p, a protein involved in Dnm1p function. Fluorescence microscopy of cells producing Dnm1-GFP or GFP-Fis1p demonstrated that both proteins had a dual localization on mitochondria and peroxisomes. Quantitative analysis revealed a greater reduction in peroxisome number in oleate-induced vps1 cells relative to dnm1 or fis1 cells. A significant fraction of oleate-induced vps1 cells still contained two or more peroxisomes. Conversely, almost all cells of a dnm1 vps1 double-deletion strain contained only one, enlarged peroxisome. This suggests that deletion of DNM1 reinforces the vps1 peroxisome phenotype. Time-lapse imaging indicated that during budding of dnm1 vps1 cells, the single peroxisome present in the mother cell formed long protrusions into the developing bud. This organelle divided at a very late stage of the budding process, possibly during cytokinesis.

GTP Phosphohydrolases↗
PubMed2005

Msp1p is an intermembrane space dynamin-related protein that mediates mitochondrial fusion in a Dnm1p-dependent manner in S. pombe.

Mitochondrial morphology is controlled by large GTPases, such as Msp1p, whose action on mitochondrial membranes is not yet understood. The sub-mitochondrial localization of Msp1p, the subject of ongoing controversies, was found to be within the intermembrane space. Overexpression of Msp1p led to aggregation of the mitochondrial network, while its downregulation resulted in fragmentation of this network. Mutations affecting the integrity of the Msp1p GTPase function had a dominant phenotype and induced mitochondrial fragmentation followed by mitochondrial DNA loss and cell death. These effects were not observed in cells deleted for Dnm1p, an actor in mitochondrial fission, suggesting that Msp1p is involved in the fusion of mitochondria.

Adenosine Triphosphatases↗
PubMed2005

Expression of the interferon-alpha/beta-inducible bovine Mx1 dynamin interferes with replication of rabies virus.

Rabies is a fatal anthropozoonotic viral infection of the central nervous system that remains a serious public health problem in many countries. As several animal cases of spontaneous survival to infection were reported and because type 1 interferons were shown to protect against the virus, it was suggested that innate resistance mechanisms exist. Among the antiviral proteins that are synthesized in response to interferon-alpha/beta stimulation, Mx proteins from several species are long known to block the replication of vesicular stomatitis virus (VSV). As both VSV and rabies virus belongs to the Rhabdoviridae family, this study was started with the aim to establish whether the anti-VSV activity of a mammalian Mx protein could be extended to rabies virus. This question was addressed by inoculating the virus onto a bovine Mx1 or human MxA-expressing Vero cell clone. Plaque formation was unambiguously blocked, and viral yields were reduced 100- to 1000-fold by bovine Mx1 expression for both SAG2 and SADB19 viral strains. In opposition, only SAG2 strain could be inhibited by the expression of human MxA protein. The effect of both proteins expression was then evaluated at the viral protein expression level. Again, boMx1 was able to repress protein expression in both strain, whereas only SAG2 proteins were inhibited in human MxA-expressing cells. These results suggest that protection conferred by interferon-alpha/beta against rabies could be, at least partially, attributable to the Mx pathway. Alternatively, bovine Mx1 could be unique in its ability to repress rabies virus which, if confirmed in vivo, would open an avenue for the development of new antirabies therapeutic strategies.

Animals↗
PubMed2003

Differential sublocalization of the dynamin-related protein OPA1 isoforms in mitochondria.

OPA1 is a cause gene for autosomal dominant optic atrophy and possesses eight alternative splicing variants. Here, we identified two isoforms of OPA1 proteins in HeLa cells and examined their submitochondrial localization and complex formations. RT-PCR shows that HeLa cells mainly express isoforms 7 and 1 of OPA1. Since the third cleavage site is mainly utilized in HeLa cells, the predicted molecular masses of their processed proteins are consistent with the 93- and 88-kDa proteins. Biochemical examinations indicate that both of the OPA1 isoforms are present in the intermembrane space. Submitochondrial fractionation by sucrose density-gradient centrifugation shows that the 88-kDa protein predominantly associates with the mitochondrial outer membrane, on the contrary, the 93-kDa protein associates with the inner membrane. Gel filtration analysis indicates that they compose the different molecular mass complexes in mitochondria. These differences between two isoforms of OPA1 would suggest their crucial role involved in the mitochondrial membrane formation.

Alternative Splicing↗