Function and Evolution of Ubiquitin HECT Ligases

The blueprint for enzyme structure and function resides in its amino acid sequence. Within evolutionarily‐related protein superfamilies, functional specificity and speciation are argued to arise through co‐evolving subsets (sectors) of sequence positions. Herein we investigate the functional divergence and evolution of the family of H omologous to the E 6AP C arboxyl T erminus (HECT) E3 ligases. The HECT ligase superfamily is catalytically promiscuous despite sharing a common, well‐studied catalytic cycle. Ubiquitin chain length and linkage specificity varies among family members. We use an evolutionary approach to pinpoint residues that underlie concerted interactions of HECT E3 ligases. S tatistical C oupling A nalysis (SCA) is a bioinformatics predictive method that identifies residue sectors that change in tandem during evolution within a multiple sequence alignment. Our SCA results revealed a network of co‐evolving residues within the catalytic domain that are functionally and thermodynamically coupled. Furthermore, our results suggest that the HECT domain has evolved independently of the N‐terminal targeting domains. We also find that SCA uncovers potential allosteric signaling pathways for HECT ligase enzyme function. Support or Funding Information [This work was supported by the School of Graduate Studies at LSU Health Sciences Center to A.L.H. and E.D.K.] This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .