title: Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein.
abstract: Manipulation of protein stability with small molecules is a challenge in the field of drug discovery. Here we show that cellular retinoic acid binding protein-II (CRABP-II) can be specifically degraded by a novel compound, SNIPER-4, consisting of (--)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-L-leucine methyl ester and all-trans retinoic acid that are ligands for cellular inhibitor of apoptosis protein 1 (cIAP1) and CRABP-II, respectively. Mechanistic analysis revealed that SNIPER-4 induces cIAP1-mediated ubiquitylation of CRABP-II, resulting in the proteasomal degradation. The protein knockdown strategy employing the structure of SNIPER-4 could be applicable to other target proteins.
authors.affiliation: Division of Biochemistry and Molecular Biology, National Institute of Health Sciences, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Okuhira
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Ohoka
authors.forename: Kimie
authors.initials: K
authors.lastname: Sai
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishimaki-Mogami
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Itoh
authors.forename: Minoru
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
mesh_terms: D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D034622:RNA Interference; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C529046:(-)-N-((2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl)-L-leucine methyl ester; D003432:Cross-Linking Reagents; D051034:Inhibitor of Apoptosis Proteins; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; D046988:Proteasome Endopeptidase Complex; D007930:Leucine