All CORVET and HOPS proteins are evolutionarily conserved (Fig. 2 and Table 2) [31, 32]. The core subunits VPS11 and VPS18 each have a clear homolog in all metazoans (Fig. 2A,C) [26, 28, 31, 34, 66-68]. Homologs of VPS16 have been found and characterized (Fig. 2B) [26, 31, 68]. An additional homolog (VPS16B/SPE39) should probably also be counted as a CORVET/HOPS complex subunit (Fig. 2B) [30, 69, 70]. SPE-39 was initially described in Caenorhabditis elegans, where it was found to associate with the HOPS complex [70, 71]. A homolog of SPE-39 called VPS16b or fob (full-of-bacteria) is present in Drosophila melanogaster [30, 69]. VPS33, the SM subunit, has two clear homologs in all metazoans (Fig. 2F and Table 2) [29, 31, 32, 70]. The expression of VPS33B appears to be ubiquitous, but no expression data are currently available for VPS33A . However, the genes appear to have differential effects on endosomal and lysosomal compartments [32, 70]. The cluster of VPS33 homologs (Fig. 2F) is interrupted by another SM protein, VPS45, which also acts in the endolysosomal transport [34, 72, 73]. In the initial morphological classification of vps mutants in yeast, VPS45 was found to be a member of class D, together with the CORVET subunit VPS3 . Moreover, the phenotypes of vps45 mutants are indistinguishable from those of vps3∆ strains . Vps45 has been characterized as an SM protein in S. cerevisiae. Finally, Vps45 is required for transport from the Golgi to vacuoles . The binding of Vps45 to the SNARE Tlg2, which localizes to the trans-Golgi network and endosomes, has been analyzed in detail . Interestingly, VPS45 also displayed genetic interaction with MON1–CCZ1, resulting in synthetic growth phenotypes . In C. elegans, VPS-45 is involved in early steps of the endosomal pathway, accumulating small vesicles that are indicative of a fusion defect . In phagosome maturation, RNAi of VPS-45 had similar effects to knockdown of CORVET/HOPS members, but was postulated to work in a step distinct from the HOPS complex member VPS-41 . Interactions between VPS45 and other members of the CORVET/HOPS complex have also been observed in mammals, indicating a function on early endosomes . Taken together, these results strongly suggest that VPS45 is an alternative SM protein interacting with CORVET/HOPS, and that it may play a role in endosome maturation. How the two VPS33 isoforms interact with HOPS and CORVET has not yet been established, and whether VPS45 may substitute for either or both VPS33 proteins remains to be seen.
VPS8 and VPS41, which are homologous to each other, have one clear corresponding gene in higher eukaryotes (Fig. 2D) [25, 26, 76]. VPS3 appears to be missing in C. elegans and D. melanogaster, which contain only one VPS39 homolog (Fig. 2E and Table 2) . Two VPS39 homologs are found in mammals [VPS39 and transforming growth factor β receptor-associated protein (TRAP1)] [33, 77, 78]. Currently, it is unclear whether TRAP1 is a Vps3 homolog or whether it evolved later. The question regarding the ‘missing’ VPS3 in C. elegans and D. melanogaster has two possible answers: either VPS39 takes over all functions performed by two proteins in yeast, or there is an as yet to be identified factor with low sequence homology that performs the function of VPS3/39. In the latter case, this unknown protein may have homologs in mammals, providing further possible combinations for tethering complexes.
After the description of all homologs of CORVET/HOPS subunits in metazoans, a small note on nomenclature may be useful. In this review, we use the yeast designations for CORVET and HOPS, assuming that CORVET is active on early endosomes (because of the interaction with Rab5/Vps21) and HOPS on late endosomes and lysosomes (the Rab7-positive compartments). The intermediate complexes i-CORVET and i-HOPS exist in yeast, but their exact roles have not yet been established . The proliferation of subunits in worms (C. elegans) and flies (D. melanogaster) (adding a second VPS33 subunit, and SPE39) and in mammals (TRAP1), and the possible addition of VPS45, adds many theoretically possible complexes. Not all of these probable complexes may exist in the cell at any given time, but certainly there will be more than just CORVET and HOPS. The available data appear to indicate that six-subunit complexes may be the rule, but other assemblies with specialized functions may occur. For example, VPS18 may be part of several complexes, and awareness of this fact should guide the interpretation of data on one individual single subunit.