Beta-transducin repeat-containing protein (β-TrCP) (β-TrCP)

Beta-transducin repeat-containing protein (β-TrCP) is a critical F-box protein that serves as the substrate recognition subunit of the SCF (Skp1-Cullin1-F-box) E3 ubiquitin ligase complex (Wikipedia, NIH). It mediates the polyubiquitination and subsequent proteasomal degradation of a diverse array of substrates, typically in a phosphorylation-dependent manner via a conserved DSG(X)2+nS degron motif (UniProt, NIH). Key substrates include critical regulators of the cell cycle such as Wee1, Cdc25A, and Emi1, as well as signal transduction proteins like β-catenin and IκBα (NIH, Wikipedia). Because it regulates both oncogenic and tumor-suppressive proteins, β-TrCP's role in disease is highly context-dependent; it is often overexpressed in cancers like colorectal and pancreatic cancer, where it acts as an oncogene, but can also function as a tumor suppressor by limiting Wnt signaling (NIH, ResearchGate). In drug discovery, β-TrCP is being explored as a therapeutic target for small-molecule inhibitors like GS143 and erioflorin, and as a recruiter for proteolysis-targeting chimeras (PROTACs) and molecular glues like NRX-252114 to induce the degradation of specific proteins of interest (NIH, Frontiers). Additionally, β-TrCP plays a role in viral infections, such as HIV-1, where the viral protein Vpu hijacks the ligase to degrade CD4 and tetherin (NIH, Wikipedia).

Other names

BTRCFBXW11FBXW1AFBW1AhsSlimbFWD1HOSFBW11beta-TrCPbeta-TRCPb-TrCPBeta-transducin repeat-containing E3 ubiquitin protein ligase

Inhibition of substrate recognition and ubiquitination (NIH, ResearchGate); Molecular glue-mediated enhancement of substrate degradation (Frontiers, ResearchGate); Recruitment of E3 ligase for targeted protein degradation in PROTACs (NIH); Small molecule inhibition of the WD40 substrate-binding domain (NIH, ResearchGate).