Details
| Original language | English |
|---|---|
| Pages (from-to) | 2213-2221 |
| Number of pages | 9 |
| Journal | Journal of molecular biology |
| Volume | 431 |
| Issue number | 11 |
| Early online date | 23 Apr 2019 |
| Publication status | Published - 17 May 2019 |
Abstract
BET proteins such as BRD3 are oncogenic transcriptional coactivators. SPOP binding triggers their proteasomal degradation. In both endometrial and prostate cancers, SPOP mutations occur in the MATH domain, but with opposed influence on drug susceptibility. In prostate cancer, SPOP mutations presumably cause increased BET levels, decreasing BET inhibitor drug susceptibility. As opposed, in endometrial cancer, decreased BET levels concomitant with higher BET inhibitor drug susceptibility were observed. Here, we present the to our knowledge first co-crystal structure of SPOP and a bromodomain containing protein (BRD3). Our structural and biophysical data confirm the suggested loss-of-function in prostate cancer-associated SPOP mutants and provide mechanistic explanation. As opposed to previous literature, our data on endometrial cancer-associated SPOP mutants do not show altered binding behavior compared to wild-type SPOP, indicating a more complex regulatory mechanism. SPOP mutation screening may thus be considered a valuable personalized medicine tool for effective antitumor therapy.
Keywords
- BET protein, cancer, SPOP, ubiquitination, x-ray crystallograpgy
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Biophysics
- Biochemistry, Genetics and Molecular Biology(all)
- Structural Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
Sustainable Development Goals
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In: Journal of molecular biology, Vol. 431, No. 11, 17.05.2019, p. 2213-2221.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Structural Insights into BET Client Recognition of Endometrial and Prostate Cancer-Associated SPOP Mutants
AU - Ostertag, Michael Sebastian
AU - Hutwelker, Wiebke
AU - Plettenburg, Oliver
AU - Sattler, Michael
AU - Popowicz, Grzegorz Maria
N1 - Funding information: We thank Dr. Arie Geerlof (Protein Expression and Purification Facility, HMGU)for providing materials for protein production. We gratefully acknowledge the use of the X-ray Crystallography Platform (Institute of Structural Biology, HMGU). We thank the European Synchrotron Radiation Facility (Grenoble, France)for beamline access and the Bavarian NMR Center (BNMRZ)for NMR measurement time. Author Contributions: Conception and design of experiments: M.S.O. G.M.P. M.S. Data acquisition and analysis: M.S.O. W.H. Conception and performance of chemical synthesis: W.H. O.P. Writing-original draft: M.S.O. W.H. Writing-review and editing: O.P. M.S. G.M.P. Project administration and supevision: O.P. G.M.P. M.S. Competing Interests Statement: The authors declare no competing interests.
PY - 2019/5/17
Y1 - 2019/5/17
N2 - BET proteins such as BRD3 are oncogenic transcriptional coactivators. SPOP binding triggers their proteasomal degradation. In both endometrial and prostate cancers, SPOP mutations occur in the MATH domain, but with opposed influence on drug susceptibility. In prostate cancer, SPOP mutations presumably cause increased BET levels, decreasing BET inhibitor drug susceptibility. As opposed, in endometrial cancer, decreased BET levels concomitant with higher BET inhibitor drug susceptibility were observed. Here, we present the to our knowledge first co-crystal structure of SPOP and a bromodomain containing protein (BRD3). Our structural and biophysical data confirm the suggested loss-of-function in prostate cancer-associated SPOP mutants and provide mechanistic explanation. As opposed to previous literature, our data on endometrial cancer-associated SPOP mutants do not show altered binding behavior compared to wild-type SPOP, indicating a more complex regulatory mechanism. SPOP mutation screening may thus be considered a valuable personalized medicine tool for effective antitumor therapy.
AB - BET proteins such as BRD3 are oncogenic transcriptional coactivators. SPOP binding triggers their proteasomal degradation. In both endometrial and prostate cancers, SPOP mutations occur in the MATH domain, but with opposed influence on drug susceptibility. In prostate cancer, SPOP mutations presumably cause increased BET levels, decreasing BET inhibitor drug susceptibility. As opposed, in endometrial cancer, decreased BET levels concomitant with higher BET inhibitor drug susceptibility were observed. Here, we present the to our knowledge first co-crystal structure of SPOP and a bromodomain containing protein (BRD3). Our structural and biophysical data confirm the suggested loss-of-function in prostate cancer-associated SPOP mutants and provide mechanistic explanation. As opposed to previous literature, our data on endometrial cancer-associated SPOP mutants do not show altered binding behavior compared to wild-type SPOP, indicating a more complex regulatory mechanism. SPOP mutation screening may thus be considered a valuable personalized medicine tool for effective antitumor therapy.
KW - BET protein
KW - cancer
KW - SPOP
KW - ubiquitination
KW - x-ray crystallograpgy
UR - http://www.scopus.com/inward/record.url?scp=85064992606&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2019.04.017
DO - 10.1016/j.jmb.2019.04.017
M3 - Article
C2 - 31026449
AN - SCOPUS:85064992606
VL - 431
SP - 2213
EP - 2221
JO - Journal of molecular biology
JF - Journal of molecular biology
SN - 0022-2836
IS - 11
ER -