Multimodal substrate recruitment enables CTLHMKLN1 E3 ligase to target acetylated N-, C-, and internal degrons
Abstract
The GID/CTLH family of E3 ubiquitin ligases employs several substrate receptor subunits that recruit distinct degrons, but the substrate recognition mechanisms of the CTLH MKLN1 assembly have largely remained elusive. Here, we reconstitute CTLH MKLN1 -dependent ubiquitylation of three biochemically distinct substrates – MKLN1 itself, ZMYND19, and FAM72A-recruited UNG2, and determine cryo-EM structures of each substrate bound to MKLN1. The structures reveal how MKLN1’s discoidin and Kelch β-propeller domains engage substrates through multivalent contacts. MKLN1 recruits itself through discoidin-Kelch interactions between MKLN1 dimers, forming an assembly that competes with other substrates. ZMYND19 and FAM72A each bind to MKLN1 through loops engaging the discoidin trench domain while their C-terminal Arg residues engage the MKLN1 Kelch central channel, identifying MKLN1 as an Arg/C-degron receptor. The acetylated N-terminus of UNG2 is positioned within a Y-shaped tunnel of FAM72A, defining an adaptor-mediated Ac/N-degron recognition mechanism. Thus, our data reveal how combinatorial deployment of MKLN1 discoidin and Kelch domains enable a single receptor subunit to recognize a diverse substrate repertoire, adding to a complex picture of degron recognition across the GID/CTLH family.
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BibTeX
@article{sepic2026multimodal,
title = {{Multimodal substrate recruitment enables CTLHMKLN1 E3 ligase to target acetylated N-, C-, and internal degrons}},
author = {Sara Sepic and Karthik V. Gottemukkala and Jiale Du and Samuel A. Maiwald and Jakub Chrustowicz and Eleftheria C. Papadopoulou and Luca J. Stier and Susanne von Gronau and Brenda A. Schulman},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78311-4},
url = {https://www.nature.com/articles/s41467-026-78311-4},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Multimodal substrate recruitment enables CTLHMKLN1 E3 ligase to target acetylated N-, C-, and internal degrons
AU - Sara Sepic
AU - Karthik V. Gottemukkala
AU - Jiale Du
AU - Samuel A. Maiwald
AU - Jakub Chrustowicz
AU - Eleftheria C. Papadopoulou
AU - Luca J. Stier
AU - Susanne von Gronau
AU - Brenda A. Schulman
PY - 2026
DA - 2026/10/17
JO - Nature Communications
DO - 10.1038/s41467-026-78311-4
UR - https://www.nature.com/articles/s41467-026-78311-4
AB - The GID/CTLH family of E3 ubiquitin ligases employs several substrate receptor subunits that recruit distinct degrons, but the substrate recognition mechanisms of the CTLH MKLN1 assembly have largely remained elusive. Here, we reconstitute CTLH MKLN1 -dependent ubiquitylation of three biochemically distinct substrates – MKLN1 itself, ZMYND19, and FAM72A-recruited UNG2, and determine cryo-EM structures of each substrate bound to MKLN1. The structures reveal how MKLN1’s discoidin and Kelch β-propeller domains engage substrates through multivalent contacts. MKLN1 recruits itself through discoidin-Kelch interactions between MKLN1 dimers, forming an assembly that competes with other substrates. ZMYND19 and FAM72A each bind to MKLN1 through loops engaging the discoidin trench domain while their C-terminal Arg residues engage the MKLN1 Kelch central channel, identifying MKLN1 as an Arg/C-degron receptor. The acetylated N-terminus of UNG2 is positioned within a Y-shaped tunnel of FAM72A, defining an adaptor-mediated Ac/N-degron recognition mechanism. Thus, our data reveal how combinatorial deployment of MKLN1 discoidin and Kelch domains enable a single receptor subunit to recognize a diverse substrate repertoire, adding to a complex picture of degron recognition across the GID/CTLH family.
SN - 2041-1723
ER -