FKBP51 and FKBP12.6-Novel and tight interactors of Glomulin

PLoS One. 2019 Sep 6;14(9):e0221926. doi: 10.1371/journal.pone.0221926. eCollection 2019.

Abstract

The protein factor Glomulin (Glmn) is a regulator of the SCF (Skp1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Mutations of Glmn lead to glomuvenous malformations. Glmn has been reported to be associated with FK506-binding proteins (FKBP). Here we present in vitro binding analyses of the FKBP-Glmn interaction. Interestingly, the previously described interaction of Glmn and FKBP12 was found to be comparatively weak. Instead, the closely related FKBP12.6 and FKBP51 emerged as novel binding partners. We show different binding affinities of full length and truncated FKBP51 and FKBP52 mutants. Using FKBP51 as a model system, we show that two amino acids lining the FK506-binding site are essential for binding Glmn and that the FKBP51-Glmn interaction is blocked by FKBP ligands. This data suggest FKBP inhibition as a pharmacological approach to regulate Glmn and Glmn-controlled processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Catalytic Domain
  • Mutation
  • Protein Binding
  • Tacrolimus Binding Proteins / chemistry
  • Tacrolimus Binding Proteins / genetics
  • Tacrolimus Binding Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 1B

Grants and funding

This work was supported by the M4 Award 2015 from the Bayerische Staatsministerium für Wirtschaft Verkehr und Technologie (BIO-1601-0003), the BMBF/ERA-IB grant ‘TACRODRUGS’ (031B0269B), and the Pioneer Fund Grant ‘PainStop’ (ENTEGA/Technische Universität Darmstadt) and ERA-IB7 (031B0269B) to F.H. C.M. acknowledges support by a Career Bridging Grant (Ingenium/Technische Universität Darmstadt). T. Mao was supported by the Chinese Scholarship Council and A. Hähle was supported by the Hanns-Seidel-Stiftung. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.