Disease relevance of VPS27

• A peptide sequence in this domain, PTVP, is involved in the function of Vps27 in the MVB pathway, the efficient endosomal recruitment of ESCRT-I, and is related to a motif in HIV-1 Gag protein that is capable of interacting with Tsg101, the mammalian homologue of Vps23 [1].

High impact information on VPS27

• Crystal structure of a phosphatidylinositol 3-phosphate-specific membrane-targeting motif, the FYVE domain of Vps27p [2].
• A molecular machinery that contains the ubiquitin-binding protein Hrs/Vps27 appears to be central in this sorting process [3].
• Our data establish a molecular link between Vps34 PI(3)K and several FYVE domain-containing proteins (Vac1p, Vps27p) required for vacuolar/lysosomal protein trafficking [4].
• These data support a model in which the Vps27p-Hse1p complex has multiple functions at the endosome, one of which is as a sorting receptor for ubiquitinated membrane proteins destined for degradation [5].
• The Vps27p Hse1p complex binds ubiquitin and mediates endosomal protein sorting [5].

Biological context of VPS27

• Epsins and Vps27p/Hrs contain ubiquitin-binding domains that function in receptor endocytosis [6].
• Solution structure of Vps27 UIM-ubiquitin complex important for endosomal sorting and receptor downregulation [7].
• We used NMR spectroscopy and mutagenesis studies to map the Ub-binding surface for Vps27 and Vps23 [8].
• Their yeast homologue, Hse1, and its binding protein, Vps27, are involved in the vacuolar membrane transport machinery [9].
• This protein is essential for ventral folding morphogenesis, and it shares structural similarity with Vps27p, which is involved in vacuolar protein sorting in yeast [10].

Anatomical context of VPS27

• A particularly striking pattern was observed in class E mutants (e.g., vps27) where 500-700 nm organelles (presumptive prevacuolar compartments) were intensely stained with FM 4-64 while the vacuole membrane was weakly fluorescent [11].
• Likewise, Ste3p that had accumulated in the class E compartment en route to the vacuole could progress to the vacuole upon restoration of Vps27p function indicating that the class E compartment can act as a functional intermediate [12].
• Upon restoration of Vps27p function, the Vps10p that had accumulated in the class E compartment could return to the Golgi apparatus and restore correct sorting of CPY [12].
• On the other hand, traffic to the early recycling endosome is less dependent on Rab5 homologs and does not require Vps27p [13].
• We describe a complex of Vps27p and Hse1p that localizes to endosomal compartments and is required for the recycling of Golgi proteins, formation of lumenal membranes and sorting of ubiquitinated proteins into those membranes [5].

Associations of VPS27 with chemical compounds

• Of the class E Vps proteins, both the ESCRT-I complex (composed of the class E proteins Vps23, 28, and 37) and Vps27 (mammalian hepatocyte receptor tyrosine kinase substrate, Hrs) have been shown to interact with ubiquitin, a signal for entry into the MVB pathway [1].

Physical interactions of VPS27

• Vps27 also bound Vps23 directly via two PSDP motifs present within the Vps27 COOH terminus [8].

Other interactions of VPS27

• In a yeast mutant that accumulates an exaggerated form of the prevacuolar compartment (vps27), Grd19p was observed to localize to this compartment [14].
• In this study we demonstrate that, whereas VPS45 and VPS27 are required for the vacuolar delivery of several membrane proteins, the vacuolar membrane protein alkaline phosphatase (ALP) reaches its final destination without the function of these two genes [15].
• The GFP-Ysl2p staining is sensitive to a mutation in VPS27 resulting in the formation of an aberrant class E compartment, but it is not affected by a sec7 mutation [16].
• MVP1 encodes a 59-kDa hydrophilic protein, Mvp1p, which appears to colocalize with Vps1p in vps1d and vps27 delta yeast cells [17].
• In vps27 strains defective for both anterograde and retrograde transport out of the PVC, a loss of Inp53p function markedly accelerated the rate of transport of TGN residents A-ALP and Kex2p into the PVC [18].

Analytical, diagnostic and therapeutic context of VPS27

• Immunofluorescence microscopy experiments show that the membrane-associated pool of Vps5p localizes to an endosome-like organelle that accumulates in the class E vps27 mutant [19].
• To elucidate the mechanism by which the FYVE domain interacts with PtdIns(3)P-containing membranes, we measured the membrane binding of the FYVE domains of yeast Vps27p and Drosophila hepatocyte growth factor-regulated tyrosine kinase substrate and their mutants by surface plasmon resonance and monolayer penetration analyses [20].

References