A Global Analysis of the Complex Structural Organization of KCTD Proteins and Their Functional Implications

KCTD proteins exhibit significant structural complexity, arising from their modular organization, oligomerization, and intricate biological partnerships. Although their biological importance has been assessed for two decades, the biochemical basis of their activities is only partially understood. This is certainly due to the limited structural information that was available until a few years ago. Fortunately, some recent insightful structural studies and the advent of machine-learning-based approaches are rapidly changing the scenario. By surveying the literature and structural databases and integrating this information with ad hoc 3D-structure predictions, we provide a detailed view of the structural biology of these proteins at different levels: individual domains, full-length oligomers, functional hetero-oligomers formed by different family members, and complexes with functional partners. Collectively, these surveys and analyses provide insights into the family's evolutionary history and its structure-function relationships. The family-wide coverage of structural information also indicates the extent to which structural similarities are reflected in functional analogies. Finally, the potential functional implications of the intricate architecture of these multimeric proteins and the tendency of their members to hetero-oligomerize are discussed from a functional perspective.