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Small-molecule displacement of a cryptic degron causes conditional protein degradation

2011; Nature Portfolio; Volume: 7; Issue: 8 Linguagem: Inglês

10.1038/nchembio.598

1552-4469

Kimberly M. Bonger, Ling-chun Chen, Corey W. Liu, Thomas J. Wandless,

Signaling Pathways in Disease

The synthetic compound Shield-1 can already be used to protect designed fusion proteins from degradation. The development of a new protein domain that is degraded upon addition of Shield-1 expands the compound's utility in controlling protein function and allows the simultaneous degradation and stabilization of different constructs. 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.