Abstact

CC2D1A is a multidomain scaffold protein implicated in transcriptional regulation and autosomal recessive non-syndromic intellectual disability (NSID), yet its molecular mechanism is still poorly understood due to a lack of structural information. Here, we present the crystal structure of the human CC2D1A491-810 fragment, encompassing the fourth DM14 domain, a coiled-coil region, and a C-terminal C2 domain. These elements form a compact, integrated architecture, with the C2 domain mediating symmetric dimerization through conserved electrostatic interactions. In addition, a unique antiparallel beta1-beta10 sheet connects the coiled-coil and C2 domains, stabilizing the tertiary structure. Fluorescence polarization assays reveal micromolar DNA-binding affinity, likely mediated by the basic surface of the DM14 domain. Comparison with the Drosophila homolog Lgd highlights conserved topology with added structural features, offering insights into CC2D1A's vertebrate-specific functions and NSID-related mutations.