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Updated: Sep 27, 2025

Direct Protein Delivery to Mammalian Cells Using Cell-permeable Cys2-His2 Zinc-finger Domains
Published on: March 25, 2015
The ZZ domain of HERC2 is a receptor of arginylated substrates
Adam H Tencer1, Jiuyang Liu1, Jing Zhu2
1Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
Abstract:
The E3 ubiquitin ligase HERC2 has been linked to neurological diseases and cancer, however it remains a poorly characterized human protein. Here, we show that the ZZ domain of HERC2 (HERC2ZZ) recognizes a mimetic of the Nt-R cargo degradation signal. NMR titration experiments and mutagenesis results reveal that the Nt-R mimetic peptide occupies a well-defined binding site of HERC2ZZ comprising of the negatively charged aspartic acids. We report the crystal structure of the DOC domain of HERC2 (HERC2DOC) that is adjacent to HERC2ZZ and show that a conformational rearrangement in the protein may occur when the two domains are linked. Immunofluorescence microscopy data suggest that the stimulation of autophagy promotes targeting of HERC2 to the proteasome. Our findings suggest a role of cytosolic HERC2 in the ubiquitin-dependent degradation pathways.
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