title: Small-molecule displacement of a cryptic degron causes conditional protein degradation.
abstract: The ability to rapidly regulate the functions of specific proteins in living cells is a valuable tool for biological research. Here we describe a new technique by which the degradation of a specific protein is induced by a small molecule. A protein of interest is fused to a ligand-induced degradation (LID) domain, resulting in the expression of a stable and functional fusion protein. The LID domain is comprised of the FK506- and rapamycin-binding protein (FKBP) and a 19-amino-acid degron fused to the C terminus of FKBP. In the absence of the small molecule Shield-1, the degron is bound to the FKBP fusion protein and the protein is stable. When present, Shield-1 binds tightly to FKBP, displacing the degron and inducing rapid and processive degradation of the LID domain and any fused partner protein. Structure-function studies of the 19-residue peptide showed that a 4-amino-acid sequence within the peptide is responsible for degradation.
authors: Department of Chemical & Systems Biology, Stanford University, Stanford, California, USA.
authors: Kimberly M
authors: KM
authors: Bonger
authors: Ling-chun
authors: LC
authors: Chen
authors: Corey W
authors: CW
authors: Liu
authors: Thomas J
authors: TJ
authors: Wandless
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins; D020134:Catalytic Domain; D002460:Cell Line; D003001:Cloning, Molecular; D005786:Gene Expression Regulation / Q000502:physiology; D008164:Luminescent Proteins; D051379:Mice; D008958:Models, Molecular; D009025:Morpholines / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D022021:Tacrolimus Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; D009025:Morpholines; D010455:Peptides; C540198:Shield-1 compound; C054562:yellow fluorescent protein, Bacteria; D022021:Tacrolimus Binding Proteins