Disease relevance of MDV1

• The Saccharomyces cerevisiae retroviruslike element Ty3 encodes the major structural proteins capsid (CA) and nucleocapsid in the GAG3 open reading frame [1].
• The major structural proteins capsid and nucleocapsid (NC) of the Saccharomyces cerevisiae retroviruslike element Ty3 are produced as domains within the Gag3 and Gag3-Pol3 precursor polyproteins [2].
• Like most retroviruses and retrotransposons, the retrotransposon Ty3 expresses its pol gene analog (POL3) as a translational fusion to the upstream gag analog (GAG3) [3].

High impact information on MDV1

• The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission [4].
• Mitochondrial division requires coordinated interactions among Fis1p, Mdv1p, and the Dnm1p GTPase, which assemble into fission complexes on the outer mitochondrial membrane [5].
• Furthermore, we show that conditional mutations in the Fis1p TPR-like domain cause fission complex assembly defects that are suppressed by mutations in the Mdv1p-predicted coiled coil [5].
• Here, we show that mitochondrial fragmentation and mitochondrial genome loss caused by lesions in MGM1 are suppressed by three novel mutations, gag1, gag2, and gag3 (for glycerol-adapted growth) [6].
• Gag3p was localized to mitochondria where it was found to associate as a peripheral protein on the cytosolic face of the outer membrane [6].

Biological context of MDV1

• Cells disrupted in this new gene, which we call NET2, contain a single mitochondrion that consists of a network formed by interconnected tubules, similar to the phenotype of dnm1 Delta cells [7].

Anatomical context of MDV1

• Furthermore, our results indicate that Net2p is required for proper assembly of the mitochondrial fission components to regulate organelle division [8].
• Whereas localization of Mdv1p to these structures requires Dnm1p, localization of Mdv1p to mitochondrial membranes does not [9].

Physical interactions of MDV1

• GAG3 encodes a novel WD40-repeat protein previously found to interact with Dnm1p in a two-hybrid assay [6].

Co-localisations of MDV1

• In addition, Mdv1p colocalizes with Dnm1p in fission-mediating punctate structures on the mitochondrial outer membrane [9].

Regulatory relationships of MDV1

• Overproduction of either domain of Net2p in yeast cells poisons mitochondrial fission, and the dominant-negative effect caused by the WD-repeats of Net2p is suppressed by increased levels of Dnm1p [8].

Other interactions of MDV1

• However, the localization of Dnm1p to the mitochondrial outer membrane is substantially reduced by the gag2 mutation, but unaffected by loss of Gag3p [6].
• The WD-repeats of Net2p interact with Dnm1p and Fis1p to regulate division of mitochondria [8].

Analytical, diagnostic and therapeutic context of MDV1

• Our studies suggest that mitochondrial fission is a multi-step process in which Mdv2p regulates the assembly of Dnm1p into punctate structures and together with Mdv1p functions later during fission to facilitate Dnm1p-dependent mitochondrial membrane constriction and/or division [9].
• Immunofluorescence microscopy indicates that Net2p is located in distinct, dot-like structures along the mitochondrial surface, many of which colocalize with the Dnm1 protein [7].
• Fluorescence and immunoelectron microscopy shows that Dnm1p and Net2p preferentially colocalize at constriction sites along mitochondrial tubules [7].
• Five putative cleavage sites of this protease in Ty3 GAG3 and GAG3-POL3 polyproteins were defined by amino-terminal sequence analysis [10].

References