A ubiquitin-binding CUE domain in presenilin-1 enables interaction with K63-linked polyubiquitin chains

•Presenilins contain a CUE ubiquitin-binding domain.•PS1 CUE domain mediates non-covalent binding to Lysine63-linked polyubiquitin chains.•PS1 CUE domain is dispensable for presenilin endoproteolysis and presenilin-dependent γ-secretase activity.

The presenilins (PS1 and PS2) are the catalytic component of the γ-secretase intramembrane protease complex, involved in the regulated intramembrane proteolysis of numerous type I transmembrane proteins, including amyloid precursor protein (APP) and Notch. Herein, we describe the identification and characterization of a CUE (coupling of ubiquitin conjugation to endoplasmic reticulum degradation) ubiquitin-binding domain (UBD) in PS1, and demonstrate that the CUE domain of PS1 mediates non-covalent binding to Lysine 63-linked polyubiquitin chains. Our results highlight a γ-secretase-independent function for non-covalent ubiquitin signaling in the regulation of PS1, and add new insights into the structure and function of the presenilin proteins.