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- EMDB-57385: Structure of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to ZMYND19 s... -

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Basic information

Entry
Database: EMDB / ID: EMD-57385
TitleStructure of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to ZMYND19 substrate
Map data
Sample
  • Complex: Map of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to ZMYND19 substrate
    • Protein or peptide: Ran-binding protein 9
    • Protein or peptide: Muskelin
    • Protein or peptide: Zinc finger MYND domain-containing protein 19
    • Protein or peptide: Glucose-induced degradation protein 8 homolog
  • Ligand: ZINC ION
Keywordscomplex / LIGASE
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 / nucleoplasm / membrane / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Zinc finger MYND domain-containing protein 19 / HNH endonuclease / Muskelin, N-terminal / : / Muskelin N-terminus / Ran binding protein 9/10, SPRY domain / : / Attractin/LZTR1 beta-propeller / CRA domain / CT11-RanBPM ...Zinc finger MYND domain-containing protein 19 / HNH endonuclease / 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 / MYND finger / Zinc finger MYND-type signature. / Lissencephaly type-1-like homology motif / Zinc finger, MYND-type / Zinc finger MYND-type profile. / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Kelch motif / Kelch repeat type 1 / His-Me finger superfamily / Kelch-type beta propeller / HNH nuclease / 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
Zinc finger MYND domain-containing protein 19 / Ran-binding protein 9 / Glucose-induced degradation protein 8 homolog / Muskelin
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsSepic S / Du J / Schulman BA
Funding support Germany, 1 items
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
DepositionApr 8, 2026-
Header (metadata) releaseOct 28, 2026-
Map releaseOct 28, 2026-
UpdateOct 28, 2026-
Current statusOct 28, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_57385.png

Downloads & links

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Map

FileDownload / File: emd_57385.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 384 pix.
= 315.725 Å		0.82 Å/pix.
x 384 pix.
= 315.725 Å		0.82 Å/pix.
x 384 pix.
= 315.725 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8222 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.075
Minimum - Maximum-0.011032389 - 5.5439825
Average (Standard dev.)0.0014978901 (±0.017454837)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 315.7248 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_57385_msk_1.map
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Additional map: #1

Fileemd_57385_additional_1.map
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Half map: #2

Fileemd_57385_half_map_1.map
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Half map: #1

Fileemd_57385_half_map_2.map
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Sample components

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Entire : Map of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to ZMYND19 substrate

EntireName: Map of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to ZMYND19 substrate
Components
  • Complex: Map of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to ZMYND19 substrate
    • Protein or peptide: Ran-binding protein 9
    • Protein or peptide: Muskelin
    • Protein or peptide: Zinc finger MYND domain-containing protein 19
    • Protein or peptide: Glucose-induced degradation protein 8 homolog
  • Ligand: ZINC ION

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Supramolecule #1: Map of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to ZMYND19 substrate

SupramoleculeName: Map of MKLN1-RANBP9-TWA1 CTLH subcomplex bound to ZMYND19 substrate
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #3, #2, #1, #4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Zinc finger MYND domain-containing protein 19

MacromoleculeName: Zinc finger MYND domain-containing protein 19 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.470838 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MTDFKLGIVR LGRVAGKTKY TLIDEQDIPL VESYSFEARM EVDADGNGAK IFAYAFDKNR GRGSGRLLHE LLWERHRGGV APGFQVVHL NAVTVDNRLD NLQLVPWGWR PKAEETSSKQ REQSLYWLAI QQLPTDPIEE QFPVLNVTRY YNANGDVVEE E ENSCTYYE ...String:
MTDFKLGIVR LGRVAGKTKY TLIDEQDIPL VESYSFEARM EVDADGNGAK IFAYAFDKNR GRGSGRLLHE LLWERHRGGV APGFQVVHL NAVTVDNRLD NLQLVPWGWR PKAEETSSKQ REQSLYWLAI QQLPTDPIEE QFPVLNVTRY YNANGDVVEE E ENSCTYYE CHYPPCTVIE KQLREFNICG RCQVARYCGS QCQQKDWPAH KKHCRERKRP FQHELEPER

UniProtKB: Zinc finger MYND domain-containing protein 19

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Macromolecule #2: Muskelin

MacromoleculeName: Muskelin / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.877742 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MAAGGAVAAA PECRLLPYAL HKWSSFSSTY LPENILVDKP NDQSSRWSSE SNYPPQYLIL KLERPAIVQN ITFGKYEKTH VCNLKKFKV FGGMNEENMT ELLSSGLKND YNKETFTLKH KIDEQMFPCR FIKIVPLLSW GPSFNFSIWY VELSGIDDPD I VQPCLNWY ...String:
MAAGGAVAAA PECRLLPYAL HKWSSFSSTY LPENILVDKP NDQSSRWSSE SNYPPQYLIL KLERPAIVQN ITFGKYEKTH VCNLKKFKV FGGMNEENMT ELLSSGLKND YNKETFTLKH KIDEQMFPCR FIKIVPLLSW GPSFNFSIWY VELSGIDDPD I VQPCLNWY SKYREQEAIR LCLKHFRQHN YTEAFESLQK KTKIALEHPM LTDIHDKLVL KGDFDACEEL IEKAVNDGLF NQ YISQQEY KPRWSQIIPK STKGDGEDNR PGMRGGHQMV IDVQTETVYL FGGWDGTQDL ADFWAYSVKE NQWTCISRDT EKE NGPSAR SCHKMCIDIQ RRQIYTLGRY LDSSVRNSKS LKSDFYRYDI DTNTWMLLSE DTAADGGPKL VFDHQMCMDS EKHM IYTFG GRILTCNGSV DDSRASEPQF SGLFAFNCQC QTWKLLREDS CNAGPEDIQS RIGHCMLFHS KNRCLYVFGG QRSKT YLND FFSYDVDSDH VDIISDGTKK DSGMVPMTGF TQRATIDPEL NEIHVLSGLS KDKEKREENV RNSFWIYDIV RNSWSC VYK NDQAAKDNPT KSLQEEEPCP RFAHQLVYDE LHKVHYLFGG NPGKSCSPKM RLDDFWSLKL CRPSKDYLLR HCKYLIR KH RFEEKAQVDP LSALKYLQND LYITVDHSDP EETKEFQLLA SALFKSGSDF TALGFSDVDH TYAQRTQLFD TLVNFFPD S MTPPKGNLVD LITL

UniProtKB: Muskelin

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Macromolecule #3: Ran-binding protein 9

MacromoleculeName: Ran-binding protein 9 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 77.927062 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MSGQPPPPPP QQQQQQQQLS PPPPAALAPV SGVVLPAPPA VSAGSSPAGS PGGGAGGEGL GAAAAALLLH PPPPPPPATA APPPPPPPP PPPASAAAPA SGPPAPPGLA AGPGPAGGAP TPALVAGSSA AAPFPHGDSA LNEQEKELQR RLKRLYPAVD E QETPLPRS ...String:
MSGQPPPPPP QQQQQQQQLS PPPPAALAPV SGVVLPAPPA VSAGSSPAGS PGGGAGGEGL GAAAAALLLH PPPPPPPATA APPPPPPPP PPPASAAAPA SGPPAPPGLA AGPGPAGGAP TPALVAGSSA AAPFPHGDSA LNEQEKELQR RLKRLYPAVD E QETPLPRS WSPKDKFSYI GLSQNNLRVH YKGHGKTPKD AASVRATHPI PAACGIYYFE VKIVSKGRDG YMGIGLSAQG VN MNRLPGW DKHSYGYHGD DGHSFCSSGT GQPYGPTFTT GDVIGCCVNL INNTCFYTKN GHSLGIAFTD LPPNLYPTVG LQT PGEVVD ANFGQHPFVF DIEDYMREWR TKIQAQIDRF PIGDREGEWQ TMIQKMVSSY LVHHGYCATA EAFARSTDQT VLEE LASIK NRQRIQKLVL AGRMGEAIET TQQLYPSLLE RNPNLLFTLK VRQFIEMVNG TDSEVRCLGG RSPKSQDSYP VSPRP FSSP SMSPSHGMNI HNLASGKGST AHFSGFESCS NGVISNKAHQ SYCHSNKHQS SNLNVPELNS INMSRSQQVN NFTSND VDM ETDHYSNGVG ETSSNGFLNG SSKHDHEMED CDTEMEVDSS QLRRQLCGGS QAAIERMIHF GRELQAMSEQ LRRDCGK NT ANKKMLKDAF SLLAYSDPWN SPVGNQLDPI QREPVCSALN SAILETHNLP KQPPLALAMG QATQCLGLMA RSGIGSCA F ATVEDYLH

UniProtKB: Ran-binding protein 9

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Macromolecule #4: Glucose-induced degradation protein 8 homolog

MacromoleculeName: Glucose-induced degradation protein 8 homolog / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 30.796715 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MSYAEKPDEI TKDEWMEKLN NLHVQRADMN RLIMNYLVTE GFKEAAEKFR MESGIEPSVD LETLDERIKI REMILKGQIQ EAIALINSL HPELLDTNRY LYFHLQQQHL IELIRQRETE AALEFAQTQL AEQGEESREC LTEMERTLAL LAFDSPEESP F GDLLHTMQ ...String:
MSYAEKPDEI TKDEWMEKLN NLHVQRADMN RLIMNYLVTE GFKEAAEKFR MESGIEPSVD LETLDERIKI REMILKGQIQ EAIALINSL HPELLDTNRY LYFHLQQQHL IELIRQRETE AALEFAQTQL AEQGEESREC LTEMERTLAL LAFDSPEESP F GDLLHTMQ RQKVWSEVNQ AVLDYENRES TPKLAKLLKL LLWAQNELDQ KKVKYPKMTD LSKGVIEEPK SDENLYFQSG WS HPQFEKG GGSGGGSGGS AWSHPQFEK

UniProtKB: Glucose-induced degradation protein 8 homolog

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.0 µm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 1073034
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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