4.7 Article

The ZZ domain of HERC2 is a receptor of arginylated substrates

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SCIENTIFIC REPORTS
卷 12, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41598-022-10119-w

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资金

  1. NIH [GM125195, GM135671, HL151334, CA252707, AG067664, GM126900]
  2. MEXT/JSPS KAKENHI [17H03585]
  3. T32 from the NIH [T32CA009156]
  4. Grants-in-Aid for Scientific Research [17H03585] Funding Source: KAKEN

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The ZZ domain of HERC2 recognizes a mimetic of the Nt-R cargo degradation signal, and the crystal structure of the DOC domain of HERC2 is reported. The study also reveals that autophagy stimulation promotes HERC2 targeting to the proteasome, indicating the role of HERC2 in the ubiquitin-dependent degradation pathways.
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 (HERC2(ZZ)) 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 HERC2(ZZ) comprising of the negatively charged aspartic acids. We report the crystal structure of the DOC domain of HERC2 (HERC2(DOC)) that is adjacent to HERC2(ZZ) 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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