High impact information on VPS4

• We characterize Vta1 as a positive regulator of Vps4 both in vivo and in vitro [1].
• Lastly, overexpression of the coiled-coil domain of Osh7p (Osh7pCC) resulted in a multivesicular body sorting defect, suggesting a dominant negative role of Osh7pCC possibly through inhibiting Vps4p function [2].
• The Vps4p AAA ATPase regulates membrane association of a Vps protein complex required for normal endosome function [3].
• This suggests that ATP hydrolysis drives a cycle of association and dissociation of Vps4p dimers/decamers [3].
• The vacuolar protein sorting (vps) mutant vps4 accumulates vacuolar, endocytic and late-Golgi markers in an aberrant multilamellar pre-vacuolar compartment [4].

Biological context of VPS4

• Though csc1-1 mutation is recessive, cells of delta csc1 do not induce autophagy in rich media, suggesting that csc1-1 allele is not a complete loss-of-function [5].
• The VPS4 gene is involved in protein transport out of a yeast pre-vacuolar endosome-like compartment [6].
• Based on the pleiotropic phenotype of the vps4 mutants and on the sequence homology to NSF/Sec18p, we propose that the VPS4 gene product is required for efficient transport out of the pre-vacuolar endosome-like compartment [6].
• The VPS4 gene product shows homology to the yeast Sec18p (50% similarity and 25% identity), which is involved in several vesicle-mediated protein transport steps and homotypic membrane fusion events [6].
• In a yeast two-hybrid screen with Vps4p as bait we isolated VPS20 (YMR077c) and the novel open reading frame YLR181c, for which the name VTA1 has recently been assigned (Saccharomyces Genome Database) [7].

Anatomical context of VPS4

• Sorting of M-C6-NBD-PC to the vacuole is blocked by energy-depletion and by null mutations in the VPS4 and VPS28 genes required for vesicular traffic from the pre-vacuolar compartment (PVC) to the vacuole [8].
• Rim20-GFP foci seem to represent endosomes, because they colocalize with Snf7-RFP and because they correspond to a perivacuolar compartment in the vps4 strain [9].
• Deletion of the VPS4 gene did not affect selective peroxisome degradation [10].
• We hypothesize that accumulation of Vps24 on membranes occurs when membrane association (dependent on interaction of phosphatidylinositol 3,5-bisphosphate with the N-terminal domain of the protein) is uncoupled from membrane disassociation (driven by Vps4p) [11].
• We find, however, that the end13 mutants have defects in transport of endocytosed fluorescent dyes, plasma membrane receptors and ligands from small peripherally located early endosomes to larger late endosomes, which are often located adjacent to the vacuole [12].

Associations of VPS4 with chemical compounds

• The Vps4 protein was purified and shown to exhibit an N-ethylmaleimide-sensitive ATPase activity [4].
• We also report that the end13-1 mutation is a serine 335 to phenylalanine substitution in the AAA-ATPase domain of End13p/Vps4p [12].

Physical interactions of VPS4

• Vps20p and Vta1p interact with Vps4p and function in multivesicular body sorting and endosomal transport in Saccharomyces cerevisiae [7].

Regulatory relationships of VPS4

• We propose that Vps20p and Vta1p regulate Vps4p function in vivo [7].
• Vta1p and Vps46p regulate the membrane association and ATPase activity of Vps4p at the yeast multivesicular body [13].

Other interactions of VPS4

• However, in cells lacking the Vps4/Did6 ATPase, a large fraction of Doa4-green fluorescent protein, like several other Vps factors, concentrates at the late endosome-like class E compartment adjacent to the vacuole [14].
• We identified C. albicans homologs to S. cerevisiae Snf7p, Vps4p, and Bro1p and generated mutants in the cognate gene [15].

Analytical, diagnostic and therapeutic context of VPS4

• Immunofluorescence indicated that both proteins function with Vps4p at a common endosomal compartment [3].

References