Protein-protein interaction networks (PPIs) are usually scale-free networks that contain a small number of highly connected nodes (hubs) and many poorly connected nodes. However, the molecular mechanisms that underlie the promiscuous interactions of hub proteins remain largely unknown. Here, we show that the floral homeotic MADS-domain transcription factor SEPALLATA3 from Arabidopsis thaliana can act as a hub in the PPI controlling flower development because it contains leucine residues at inter- and intramolecular interaction interfaces. Comprehensive sequence analyses of diverse MADS-domain proteins indicate exceedingly high conservation of the identified leucine residues within SEPALLATA-subfamily proteins, whereas non-hub MADS-domain proteins exhibit preferences for other amino acids at homologous sites. Our results indicate that the conservation of leucine residues at positions critical for protein-protein interactions contributed significantly to the present-day structure of the PPI and may have facilitated the evolution of the flower.