Programmable protein degraders enable selective knockdown of pathogenic β-catenin subpopulations <i>in vitro</i> and <i>in vivo</i>.

ABSTRACT: Aberrant activation of Wnt signaling results in unregulated accumulation of cytosolic β-catenin, which subsequently enters the nucleus and promotes transcription of genes that contribute to cellular proliferation and malignancy. Here, we sought to eliminate pathogenic β-catenin from the cytosol using designer ubiquibodies (uAbs), chimeric proteins composed of an E3 ubiquitin ligase and a target-binding domain that redirect intracellular proteins to the proteasome for degradation. To accelerate uAb development, we leveraged a protein language model (pLM)-driven algorithm called SaLT&PepPr to computationally design "guide" peptides with affinity for β-catenin, which were subsequently fused to the catalytic domain of a human E3 called C-terminus of Hsp70-interacting protein (CHIP). Expression

SUBMITTER: Ye T 

PROVIDER: S-EPMC11601283 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature