A flexible loop in the Smc3 head domain is required for stability and cohesin complex integrity

Smc3 is a core subunit of the cohesin complex and is essential for its biological function. Cohesin, an evolutionarily conserved complex of the Structural Maintenance of Chromosomes (SMC) family, mediates the higher-order organization of chromatin and plays a crucial role in maintaining genome stability and dynamics. Mutations in human SMC3 are associated with Cornelia de Lange syndrome (CdLS), a rare genetic disorder characterized by cognitive and physical developmental delays. This study identified a flexible loop within the head domain of Smc3 and investigated its function. This loop was demonstrated to have an essential role in cohesin activity, specifically by mediating the interaction with the kleisin subunit Scc1. Deletion of this loop or mutation of residues within it destabilizes the protein, affecting cohesion and its enrichment on chromatin in cells. By assigning a functional role to this loop region, single-nucleotide variants of unknown clinical significance (VUS), previously identified in Cornelia de Lange syndrome patients, can be re-examined and suggested for classification as pathogenic. This work enhances the understanding of the structure-function relationship of Smc3 and its impact on human health.