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- PDB-31tm: Structure of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to FAM72A C-... -

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Basic information

Entry
Database: PDB / ID: 31tm
TitleStructure of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to FAM72A C-terminus
Components
  • Glucose-induced degradation protein 8 homolog
  • Muskelin
  • Protein FAM72A
  • Ran-binding protein 9
KeywordsLIGASE / complex
Function / homology
Function and homology information


postsynaptic specialization membrane of symmetric synapse / postsynaptic endosome membrane / neurotransmitter receptor transport postsynaptic membrane to endosome / L1CAM interactions / GID complex / regulation of receptor internalization / positive regulation of amyloid precursor protein catabolic process / microtubule nucleation / microtubule associated complex / cell-matrix adhesion ...postsynaptic specialization membrane of symmetric synapse / postsynaptic endosome membrane / neurotransmitter receptor transport postsynaptic membrane to endosome / L1CAM interactions / GID complex / regulation of receptor internalization / positive regulation of amyloid precursor protein catabolic process / microtubule nucleation / microtubule associated complex / cell-matrix adhesion / MET activates RAS signaling / cytoskeleton organization / ruffle / ubiquitin ligase complex / Regulation of pyruvate metabolism / regulation of cell shape / negative regulation of ERK1 and ERK2 cascade / GABA-ergic synapse / cell junction / small GTPase binding / positive regulation of canonical Wnt signaling pathway / actin cytoskeleton organization / RAF/MAP kinase cascade / protein-containing complex assembly / cell cortex / proteasome-mediated ubiquitin-dependent protein catabolic process / nuclear body / postsynapse / protein-macromolecule adaptor activity / positive regulation of cell population proliferation / synapse / signal transduction / enzyme binding / protein homodimerization activity / mitochondrion / nucleoplasm / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Protein FAM72 / Yippee homolog 2 zinc finger protein / Muskelin, N-terminal / : / Muskelin N-terminus / Ran binding protein 9/10, SPRY domain / : / Attractin/LZTR1 beta-propeller / CRA domain / CT11-RanBPM ...Protein FAM72 / Yippee homolog 2 zinc finger protein / Muskelin, N-terminal / : / Muskelin N-terminus / Ran binding protein 9/10, SPRY domain / : / Attractin/LZTR1 beta-propeller / CRA domain / CT11-RanBPM / : / CTLH/CRA C-terminal to LisH motif domain / CTLH/CRA C-terminal to LisH motif domain / LisH / C-terminal to LisH motif. / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / Galactose oxidase/kelch, beta-propeller / Lissencephaly type-1-like homology motif / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Kelch motif / Kelch repeat type 1 / Kelch-type beta propeller / SPRY domain / B30.2/SPRY domain / B30.2/SPRY domain profile. / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / SPRY domain / Galactose-binding-like domain superfamily / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Protein FAM72A / Ran-binding protein 9 / Glucose-induced degradation protein 8 homolog / Muskelin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsSepic, S. / Schulman, B.A.
Funding support Germany, 1items
OrganizationGrant numberCountry
Max Planck Society Germany
CitationJournal: Nat Commun / Year: 2026
Title: Multimodal substrate recruitment enables CTLH E3 ligase to target acetylated N-, C-, and internal degrons.
Authors: Sara Sepic / Karthik V Gottemukkala / Jiale Du / Samuel A Maiwald / Jakub Chrustowicz / Eleftheria C Papadopoulou / Luca J Stier / Susanne von Gronau / Brenda A Schulman /
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 ...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.
History
DepositionJun 23, 2026Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 28, 2026Provider: repository / Type: Initial release
Revision 1.0Oct 28, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein FAM72A
B: Muskelin
F: Ran-binding protein 9
E: Glucose-induced degradation protein 8 homolog


Theoretical massNumber of molelcules
Total (without water)210,2384
Polymers210,2384
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Protein FAM72A / Latent membrane protein 1-induced protein / LMP1-induced protein / LMPIP


Mass: 16636.326 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FAM72A, UGENE / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q5TYM5
#2: Protein Muskelin


Mass: 84877.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MKLN1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9UL63
#3: Protein Ran-binding protein 9 / RanBP9 / BPM-L / BPM90 / Ran-binding protein M / RanBPM / RanBP7


Mass: 77927.062 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RANBP9, RANBPM / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96S59
#4: Protein Glucose-induced degradation protein 8 homolog / Two hybrid-associated protein 1 with RanBPM / Twa1


Mass: 30796.715 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GID8, C20orf11, TWA1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9NWU2
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Structure of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to FAM72A C-terminus
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2600 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX2.0_5936model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 358574 / Symmetry type: POINT
RefinementHighest resolution: 3.7 Å / Cross valid method: NONE
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027684
ELECTRON MICROSCOPYf_angle_d0.4310489
ELECTRON MICROSCOPYf_dihedral_angle_d3.4071094
ELECTRON MICROSCOPYf_chiral_restr0.0351202
ELECTRON MICROSCOPYf_plane_restr0.0041357

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