29UE

Focus refined structure of CTLH E3-MKLN1 and substrate-MKLN1 dimer

Summary for 29UE

• Entry DOI: 10.2210/pdb29ue/pdb
• EMDB information: 57377
• Descriptor: Muskelin (1 entity in total)
• Functional Keywords: complex, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 169755.48

Authors

Sepic, S.,Chrustowicz, J.,Du, J.,Schulman, B.A. (deposition date: 2026-04-08, release date: 2026-10-28)

Primary citation

Sepic, S.,Gottemukkala, K.V.,Du, J.,Maiwald, S.A.,Chrustowicz, J.,Papadopoulou, E.C.,Stier, L.J.,von Gronau, S.,Schulman, B.A.
Multimodal substrate recruitment enables CTLH MKLN1 E3 ligase to target acetylated N-, C-, and internal degrons.
Nat Commun, 17:-, 2026

PubMed 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 assembly have largely remained elusive. Here, we reconstitute CTLH-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.

PubMed: 42892655
DOI: 10.1038/s41467-026-78311-4

Experimental method

ELECTRON MICROSCOPY (3.7 Å)