9l8y
Crystal structure of HERC2
Structural highlights
FunctionHERC2_HUMAN E3 ubiquitin-protein ligase that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes. Recruited to sites of DNA damage in response to ionizing radiation (IR) and facilitates the assembly of UBE2N and RNF8 promoting DNA damage-induced formation of 'Lys-63'-linked ubiquitin chains. Acts as a mediator of binding specificity between UBE2N and RNF8. Involved in the maintenance of RNF168 levels. E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of XPA which influences the circadian oscillation of DNA excision repair activity.[1] [2] [3] Publication Abstract from PubMedNCOA4, a dedicated autophagy receptor for mediating selective autophagy of ferritin (ferritinophagy), plays a vital role in maintaining cellular iron homeostasis. The cellular abundance of NCOA4 is regulated by the E3 ligase HERC2 that can specifically target NCOA4 for proteasomal degradation under iron-replete conditions. However, the detailed molecular mechanism governing the iron-dependent recognition of NCOA4 by HERC2 remains elusive. Here, using multidisciplinary approaches, we systematically characterize the HERC2-binding domain (HBD) of NCOA4 and its interaction with HERC2. We uncover that NCOA4 HBD harbors a [2Fe-2S] cluster and can exist in two different states, the apo-form state and the [2Fe-2S] cluster-bound state. Moreover, we unravel that HERC2 can effectively recognize the [2Fe-2S] cluster-bound NCOA4 HBD through its Cullin-7-PARC-HERC2 (CPH) domain and iron-sulfur cluster-dependent NCOA4-binding domain (INBD) with a synergistic binding mode. The determined crystal structures of HERC2(2540-2700) and its complex with the [2Fe-2S] cluster-bound NCOA4 HBD together with relevant biochemical and cellular results not only elucidate how NCOA4 HBD specifically senses cellular iron level by binding a [2Fe-2S] cluster but also reveal the molecular basis underlying the specific interaction of HERC2 with the [2Fe-2S] cluster-bound NCOA4 HBD. In summary, our findings provide mechanistic insights into the iron-dependent turnover of NCOA4 by HERC2 and expand our understanding of the regulatory mechanism of NCOA4-mediated ferritinophagy. Mechanistic insights into the iron-sulfur cluster-dependent interaction of the autophagy receptor NCOA4 with the E3 ligase HERC2.,Liu H, Shen L, Gong X, Zhou X, Huang Y, Zhou Y, Guo Z, Guo H, Wang S, Pan L Proc Natl Acad Sci U S A. 2025 Jul 29;122(30):e2510269122. doi: , 10.1073/pnas.2510269122. Epub 2025 Jul 24. PMID:40705422[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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