Fig. 1

Domain organization of the different human members of the Cdc48 family. The tandem D-domains, D1 and D2, are shown in grey. N-domains with φβ double barrel fold are shown in green; the deviating N-terminal domain of nuclear VCP-like (NVL) is shown as a white box. The putative second N-domains of Pex1 (N2) and of Pex6 (N1) are highlighted by dashed boxes. The larger inserts into the D1-domain of NVL and the D2-domain of Pex1 are shown in brown. The tail helices at the C-terminal end of D2-domains are indicated as black boxes. The bromodomain in the D2-domain of Yta7 is shown in blue and is located right after the N-terminal subdomain containing the Rossman fold. Note that vertebrates generally possess two Yta7 homologs, referred to as ATAD2 and ATAD2B; only one of the two human Yta7 variants is shown. Note that the detailed arrangement of the secondary structural elements of the two D-domains of Cdc48 is given in Additional file 3: Figure S2. The novel family member Spaf-like has been discovered in screens for chronic kidney disease [113, 114] and has also been found in several interactome studies (e.g. [64, 115–117], suggesting that it plays a role in selective protein degradation. Spaf-like constitutes a distinctive branch that has been not recognized clearly in earlier surveys, probably because this factor is present in only a few eukaryotic lineages. Generally, its domain structure is similar to that of Cdc48. However, as noted earlier [19], Spaf-like from Arabidopsis thaliana has no N-domain and contains a transmembrane region at its C-terminal end. As more sequence information is now available, we found that a C-terminal transmembrane region is shared by all Spaf-like from core eudicots, suggesting that the membrane anchor was gained in this lineage. By contrast, the loss of the N-domain appears to have occurred much earlier in plants, as we did not find it in most plants, apart from the green algae group Mamiellales (Ostreococcus, Micromonas). It cannot be excluded, however, that the absence of this domain in some species is caused by incomplete sequence assembly. Recurrently, we came across a few more diverged double-ring AAA ATPase sequences that formed longer branches in our phylogenetic trees and that appear to be more closely related to Cdc48 than to any other member of the family. As we discovered these sequences in several diverse lineages, including heterokonts, amoebozoa, a few green algae, and basal fungi, but not in animals, they might constitute another basal family member. We named this factor Cdc48-like, but cannot currently exclude the possiblity that Cdc48-like is a collection of more diverged Cdc48 variants that group together because of long-branch attraction