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The conserved HECT domain (which comprises ~350 amino acids) is located at the C-terminus of the E3 ligases of the homologous to the E6AP carboxyl terminus (HECT) domain family.The HECT domain itself is bi-lobed, consisting of an N-terminal N-lobe that interacts with the E2 and a C-terminal C-lobe that contains the active-site cysteine that forms the thioester with ubiquitin.The model of ubiquitin transfer from the thioesters of E2s to the active-site cysteine has been revealed.However, the mechanism underlying this ubiquitintransfer is poorly understood.By using an algorithm that detects coevolving residues within a protein family, called statistical coupling analysis (SCA), we identified and characterized three clusters of coevolving and functionally linked residues within HECT domain which locate in different lobes and span its E2-binding and ubiquitin-binding sites.The results may provide a necessary foundation for understanding the mechanism of the ubiquitin transfer .