7klz

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Structure of SPOP MATH domain in complex with a Geminin peptide

Structural highlights

7klz is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.4Å
Ligands:PO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SPOP_HUMAN Inhibits IPF1/PDX1 transactivation of established target promoters, such as insulin, may be by recruiting a repressor complex (By similarity). In complex with CUL3, involved in ubiquitination of BMI1, H2AFY and DAXX, and probably also in ubiquitination and proteasomal degradation of Gli2 or Gli3.[1] [2] [3]

Publication Abstract from PubMed

Geminin and its binding partner Cdt1 are essential for the regulation of DNA replication. Here we show that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP binds Geminin at endogenous level and regulates DNA replication. SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication. SPOP is frequently mutated in certain human cancer types and implicated in tumorigenesis. We show that cancer-associated SPOP mutations impair Geminin K27-linked poly-ubiquitination and induce replication origin over-firing and re-replication. The replication stress caused by SPOP mutations triggers replication catastrophe and cell death upon ATR inhibition. Our results reveal a tumor suppressor role of SPOP in preventing DNA replication over-firing and genome instability and suggest that SPOP-mutated tumors may be susceptible to ATR inhibitor therapy.

SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition.,Ma J, Shi Q, Cui G, Sheng H, Botuyan MV, Zhou Y, Yan Y, He Y, Wang L, Wang Y, Mer G, Ye D, Wang C, Huang H Nat Commun. 2021 Oct 1;12(1):5779. doi: 10.1038/s41467-021-26049-6. PMID:34599168[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
4 reviews cite this structure
Non-proteolytic ubiquitylation in cellular signaling and human disease.
Liao et al. (2022)
3 more
6 other articles
No citations found

See Also

References

  1. ↑ Furukawa M, He YJ, Borchers C, Xiong Y. Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol. 2003 Nov;5(11):1001-7. Epub 2003 Oct 5. PMID:14528312 doi:10.1038/ncb1056
  2. ↑ Hernandez-Munoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E, Nusinow DA, Panning B, Marahrens Y, van Lohuizen M. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40. Epub 2005 May 16. PMID:15897469 doi:0408918102
  3. ↑ Kwon JE, La M, Oh KH, Oh YM, Kim GR, Seol JH, Baek SH, Chiba T, Tanaka K, Bang OS, Joe CO, Chung CH. BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase. J Biol Chem. 2006 May 5;281(18):12664-72. Epub 2006 Mar 8. PMID:16524876 doi:10.1074/jbc.M600204200
  4. ↑ Ma J, Shi Q, Cui G, Sheng H, Botuyan MV, Zhou Y, Yan Y, He Y, Wang L, Wang Y, Mer G, Ye D, Wang C, Huang H. SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition. Nat Commun. 2021 Oct 1;12(1):5779. PMID:34599168 doi:10.1038/s41467-021-26049-6

Contents


PDB ID 7klz

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