Hereditary spastic paraplegia protein spartin is an FK506-binding protein identified by mRNA display

Mayuko Tokunaga, Hirokazu Shiheido, Ichigo Hayakawa, Akiko Utsumi, Hideaki Takashima, Nobuhide Doi, Kenichi Horisawa, Yuko Sakuma-Yonemura, Noriko Tabata, Hiroshi Yanagawa

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Abstract

Here, we used mRNA display to search for proteins that bind to FK506, a potent immunosuppressant drug, and identified spartin, a hereditary spastic paraplegia protein, from a human brain cDNA library. We demonstrated that FK506 binds to the C-terminal region of spartin and thereby inhibits the interaction of spartin with TIP47, one of the lipid droplet-associated proteins. We further confirmed that FK506 inhibits localization of spartin and its binder, an E3 ubiquitin ligase AIP4, in lipid droplets and increases the protein level of ADRP (adipose differentiation-related protein), which is a regulator of lipid homeostasis. These results strongly suggest that FK506 suppresses the proteasomal degradation of ADRP, a substrate of AIP4, by inhibiting the spartin-TIP47 interaction and thereby blocking the localization of spartin and AIP4 in lipid droplets.

Original languageEnglish
Pages (from-to)935-942
Number of pages8
JournalChemistry and Biology
Volume20
Issue number7
DOIs
Publication statusPublished - 2013 Jul 25

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Tokunaga, M., Shiheido, H., Hayakawa, I., Utsumi, A., Takashima, H., Doi, N., Horisawa, K., Sakuma-Yonemura, Y., Tabata, N., & Yanagawa, H. (2013). Hereditary spastic paraplegia protein spartin is an FK506-binding protein identified by mRNA display. Chemistry and Biology, 20(7), 935-942. https://doi.org/10.1016/j.chembiol.2013.05.011