Alix is a phylogenetically conserved protein that participates in mammals in programmed cell death in association with ALG-2, a penta-EF-hand calciprotein. It contains an N-terminal Bro1 domain, a coiled-coil region and a C-terminal proline-rich domain containing several SH3- and WW-binding sites that contribute to its scaffolding properties. Recent data showed that by virtue of its Bro1 domain, Alix is functionally associated to the ESCRT complexes involved in the biogenesis of the multivesicular body and sorting of transmembrane proteins within this specific endosomal compartment. In Dictyostelium, an alx null strain shows a markedly perturbed starvation-induced morphogenetic program while ALG-2 disruptants remain unaffected. This review summarizes Dictyostelium data on Alix and ALG-2 homologues and evaluates whether known functions of Alix in other organisms can account for the developmental arrest of the alx null mutant and how Dictyostelium studies can substantiate the current understanding of the function(s) of this versatile and conserved signaling molecule.
"Not only do many of the genes encoding ESCRT subunits appear to have caretaker functions, with mutations being linked to both cancer and neurological disorders, these genes also have an origin pre-dating the metazoan lineage (reviewed by Ilievska et al., 2011). Model organisms, such as the amoeba, Dictyostelium discoideum (Annesley & Fisher, 2009; Williams RS et al., 2006), can therefore be used to study the fundamental molecular roles of these proteins (Blanc et al., 2009; Mattei et al., 2006). Overall, the evolutionary age of cancer genes parallels their role in human cancer etiology (Fig. 4). "
"EXP-1 is a well-characterized integral membrane protein localized to the parasitophorous vacuole [43,44]. PDCD6IP/ALIX is a class E vacuolar sorting protein involved in the transport of cargo proteins by the multivesicular body for incorporation into intralumenal vesicles; fusion between endosomes and the vacuole results in the localization of cargo proteins to the vacuolar lumen . In addition, PDCD6IP/ALIX is used by several viruses, including HIV-1, for exiting infected cells . "
[Show abstract][Hide abstract] ABSTRACT: In order to establish a successful infection in the human host, the malaria parasite Plasmodium falciparum must establish interactions with a variety of human proteins on the surface of different cell types, as well as with proteins inside the host cells. To better understand this aspect of malaria pathogenesis, a study was conducted with the goal of identifying interactions between proteins of the parasite and those of its human host.
A modified yeast two-hybrid methodology that preferentially selects protein fragments that can be expressed in yeast was used to conduct high-throughput screens with P. falciparum protein fragments against human liver and cerebellum libraries. The resulting dataset was analyzed to exclude interactions that are not likely to occur in the human host during infection.
An initial set of 2,200 interactions was curated to remove proteins that are unlikely to play a role in pathogenesis based on their annotation or localization, and proteins that behave promiscuously in the two-hybrid assay, resulting in a final dataset of 456 interactions. A cluster that implicates binding between P. falciparum PFE1590w/ETRAMP5, a putative parasitophorous vacuole membrane protein, and human apolipoproteins ApoA, ApoB and ApoE was selected for further analysis. Different isoforms of ApoE, which are associated with different outcomes of malaria infection, were shown to display differential interactions with PFE1590w.
A dataset of interactions between proteins of P. falciparum and those of its human host was generated. The preferential interaction of the P. falciparum PFE1590w protein with the human ApoE epsilon3 and ApoE epsilon4 isoforms, but not the ApoE epsilon2 isoform, supports the hypothesis that ApoE genotype affects risk of malaria infection. The dataset contains other interactions of potential relevance to disease that may identify possible vaccine candidates and drug targets.
"Not only do many of the genes encoding ESCRT subunits appear to have caretaker functions, with mutations linked to cancer and neurological disorders, these genes also have an origin pre-dating the metazoan lineage (reviewed by Ilievska et al., 2011). Model organisms, such as the amoeba, Dictyostelium discoideum (Annesley & Fisher, 2009; Williams RS et al., 2006), can therefore be used to study the fundamental molecular roles of these proteins (Blanc et al., 2009; Mattei et al., 2006). Overall, the evolutionary age of cancer genes parallels their role in human cancer etiology (Fig. 4). "
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