Multimodal substrate recruitment enables CTLH(MKLN1) E3 ligase to target acetylated N-, C-, and internal degrons.

MKLN1 within the CTLH E3 ligase recognizes diverse substrates through multimodal engagement of acetylated, Arg, and C-degrons, revealing a versatile recognition mechanism.

• Why it matters: Understanding substrate recognition by E3 ligases is crucial for elucidating protein degradation pathways, yet the mechanisms of MKLN1's substrate specificity have remained unclear.
• What they did: Researchers reconstituted MKLN1-dependent ubiquitylation of three substrates—MKLN1, ZMYND19, and UNG2—and determined cryo-EM structures showing how MKLN1's discoidin and Kelch domains engage these substrates via multivalent contacts.
• The result: The findings demonstrate that MKLN1's domains enable recognition of a broad substrate spectrum, including acetylated N-termini and Arg/C-degrons, providing insight into its versatile degron targeting capabilities.