Crystal structure of transcription factor MaIT domain III: A novel helix repeat fold implicated in regulated oligomerization

Background: MalT from Escherichia coli, the best-studied member of the MalT family of ATP-dependent transcriptional activators, regulates the genes fo r maltooligosaccharide utilization. The active form of this 4 domain protei n is a homooligomer, and its multimerization is induced by the binding of m altotriose. Domains II and III of MalT were suggested to mediate the oligom erization process, but its molecular mechanism and the specific functions o f these domains remain to be identified. Results: We solved the crystal structure of MalT domain III at 1.45 Angstro m resolution by multiple isomorphous replacement phasing. The structure rev eals eight copies of a two-helix bundle motif arranged in a novel, right-ha nded superhelix fold with closed walls, followed by a small C-terminal subd omain. The MalT superhelix contains a potential maltotriose binding site an d forms a large hydrophobic protein-protein interaction interface that medi ates the contact between two MalT domain III molecules. Structure-based ana lysis of the two-helix bundle motifs revealed a novel degenerated sequence pattern, and repeats of this pattern could be identified in other regulator proteins. Conclusions: MalT domain III contains a novel superhelix fold. Its protein- protein interaction interface, however, resembles protein binding sites of other superhelical proteins, suggesting a model with domain III mediating M alT oligomerization. Maltotriose seems to modulate the interaction interfac e and MalT oligomerization by occupying the ligand binding site inside the superhelix. Similar structural and mechanistic features in other MalT prote in-family members and unrelated regulator proteins are indicated by the rea ppearance of a novel sequence motif derived from the MalT domain III struct ure.