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 -