The MSD Hydroxyzine dihydrochloride domain has been previously computationally predicted to assume an RNase H-like fold. In agreement with these studies, Robetta utilized an exonuclease structure as a parent molecule for this domain. The C-terminal sequence of MAEL protein was modeled denovo as it appears unique. The predicted structure shows the HMGbox domain on the surface and not encapsulated by the rest of the molecule. Instead, it is connected with the MSD domain by an approximately 30-residue linker region that appears devoid of any secondary structural elements. Based on the sequence composition, this linker region is predicted to have high propensity for intrinsic disorder, which could account for insolubility that we have encountered while attempting to purify recombinant full-length or truncated Maelstrom proteins. The fact that the MAEL HMG-box domain is not buried, but instead connected to rest of the protein with an unstructured linker reaf firmed our interest in understanding its function. To infer the domain relationships, we performed multiple sequence alignment of candidate HMG-box domains from SS and NSS groups with the mouse, human and Drosophila Mael HMG-box domains. This analysis showed that the MAEL HMG-box domains form a separate branch on the phylogenic tree. In addition to the described structural differences specific to the mammalian MAELHMG-box domain, this implies that there are other features common to the MAELHMG-box domain homologues that maybe important. The MAEL HMG-box domains are most closely related to domain A of non-sequence specific binders, but differ from these in their distribution of charged residues. In the mammalian MAEL HMG-box domains, the loop connecting helices-1 and 2 does not contain charged residues, and helix-2 is devoid of the positively charged residues that are present in all other groups. While charged residues in other domains seem to be alternating fromhelix-1 to helix-2,the mammalian MAELHMG-box domain has concentrated positive residues, which form a novel region.The distribution of charged residuesis Piceatannol indicative of an H-bond potential that, together with non-polarregions, can provide the biochemical basis for strong interactions with appropriate substrates. These features vary in Drosophila Mael HMG-box domain that is still distinct from canonical HMG-boxes.