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| Title | Molecular mechanisms of assembly and TRIP13-mediated remodeling of the human Shieldin complex. |
|---|---|
| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 118, Issue 8, Year 2021 |
| Publish date | Feb 23, 2021 |
 Authors | Wei Xie / Shengliu Wang / Juncheng Wang / M Jason de la Cruz / Guotai Xu / Maurizio Scaltriti / Dinshaw J Patel /  |
| PubMed Abstract | The Shieldin complex, composed of REV7, SHLD1, SHLD2, and SHLD3, protects DNA double-strand breaks (DSBs) to promote nonhomologous end joining. The AAA ATPase TRIP13 remodels Shieldin to regulate DNA ...The Shieldin complex, composed of REV7, SHLD1, SHLD2, and SHLD3, protects DNA double-strand breaks (DSBs) to promote nonhomologous end joining. The AAA ATPase TRIP13 remodels Shieldin to regulate DNA repair pathway choice. Here we report crystal structures of human SHLD3-REV7 binary and fused SHLD2-SHLD3-REV7 ternary complexes, revealing that assembly of Shieldin requires fused SHLD2-SHLD3 induced conformational heterodimerization of open (O-REV7) and closed (C-REV7) forms of REV7. We also report the cryogenic electron microscopy (cryo-EM) structures of the ATPγS-bound fused SHLD2-SHLD3-REV7-TRIP13 complexes, uncovering the principles underlying the TRIP13-mediated disassembly mechanism of the Shieldin complex. We demonstrate that the N terminus of REV7 inserts into the central channel of TRIP13, setting the stage for pulling the unfolded N-terminal peptide of C-REV7 through the central TRIP13 hexameric channel. The primary interface involves contacts between the safety-belt segment of C-REV7 and a conserved and negatively charged loop of TRIP13. This process is mediated by ATP hydrolysis-triggered rotatory motions of the TRIP13 ATPase, thereby resulting in the disassembly of the Shieldin complex. |
 External links | Proc Natl Acad Sci U S A / PubMed:33597306 / PubMed Central |
| Methods | EM (single particle) / X-ray diffraction |
| Resolution | 2.7 - 3.8 Å |
| Structure data | EMDB-23244, PDB-7l9p:  PDB-6ww9:  PDB-6wwa: |
| Chemicals |  ChemComp-AGS: |
| Source |
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 Keywords |  NUCLEAR PROTEIN / REV7 / SHLD3 / SHLD2 / TRIP13 |
