Amyloid protein-binding protein 2 (APPBP2) (APPBP2)

Amyloid protein-binding protein 2 (APPBP2) is a substrate recognition subunit of the Cullin-2-RING E3 ubiquitin ligase (CRL2) complex (UniProt Q92481). It is a key component of the C-degron pathway, specifically identifying and targeting proteins that possess a C-terminal arginine-leucine (RL) motif, such as the RLAA sequence found at the terminus of the deubiquitinase USP1 (Lin et al., 2018, Science). This pathway serves as a quality control mechanism to degrade truncated or misfolded proteins that expose these normally internal or specific terminal sequences (Timms et al., 2019, Mol Cell). In the context of drug discovery, APPBP2 is being explored as a recruitment module for PROTACs (Proteolysis Targeting Chimeras) and other targeted protein degradation strategies. Beyond its role in protein quality control, APPBP2 has been linked to the regulation of microtubule dynamics and TGF-beta signaling. Its dysregulation is associated with various cancers and neurodegenerative conditions like Alzheimer's disease, where it interacts with the Amyloid Precursor Protein (APP). The specificity of the RLAA motif recognition makes it a valuable tool for synthetic biology and precision medicine applications.

Other names

APP-BP2PAT1Protein interacting with APP tail 1ARA67Cullin-2-APPBP2 complexCRL2-APPBP2

The E3 ligase complex recognizes the C-terminal RLAA motif (or RL motif) of a substrate protein, facilitating its polyubiquitination and subsequent degradation by the 26S proteasome.