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- PDB-8ttq: Cryo-EM structure of the inner MKLN1 dimer from an autoinhibited ... -

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Basic information

Entry
Database: PDB / ID: 8ttq
TitleCryo-EM structure of the inner MKLN1 dimer from an autoinhibited MKLN1 tetramer
ComponentsMuskelin
KeywordsLIGASE / E3 ubiquitin ligase / CTLH complex / substrate adapter recruitment / PROTEIN BINDING
Function / homology
Function and homology information


postsynaptic specialization membrane of symmetric synapse / postsynaptic endosome membrane / neurotransmitter receptor transport postsynaptic membrane to endosome / regulation of receptor internalization / vesicle-mediated transport in synapse / ubiquitin ligase complex / Regulation of pyruvate metabolism / ruffle / cell-matrix adhesion / GABA-ergic synapse ...postsynaptic specialization membrane of symmetric synapse / postsynaptic endosome membrane / neurotransmitter receptor transport postsynaptic membrane to endosome / regulation of receptor internalization / vesicle-mediated transport in synapse / ubiquitin ligase complex / Regulation of pyruvate metabolism / ruffle / cell-matrix adhesion / GABA-ergic synapse / regulation of cell shape / actin cytoskeleton organization / cell cortex / signal transduction / protein homodimerization activity / nucleoplasm / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Muskelin, N-terminal / : / Muskelin N-terminus / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / Galactose oxidase/kelch, beta-propeller / Lissencephaly type-1-like homology motif / KLHDC2/KLHL20/DRC7 Kelch-repeats domain / LIS1 homology (LisH) motif profile. / LIS1 homology motif ...Muskelin, N-terminal / : / Muskelin N-terminus / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / Galactose oxidase/kelch, beta-propeller / Lissencephaly type-1-like homology motif / KLHDC2/KLHL20/DRC7 Kelch-repeats domain / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Kelch motif / Kelch repeat type 1 / Kelch-type beta propeller / Galactose-binding-like domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsChana, C.K. / Keszei, A.F.A. / Sicheri, F.
Funding support Canada, 3items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT-178026 Canada
Canadian Institutes of Health Research (CIHR)PJT-180338 Canada
Canadian Institutes of Health Research (CIHR)PJT-186218 Canada
CitationJournal: Nat Commun / Year: 2024
Title: FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation.
Authors: Philip Barbulescu / Chetan K Chana / Matthew K Wong / Ines Ben Makhlouf / Jeffrey P Bruce / Yuqing Feng / Alexander F A Keszei / Cassandra Wong / Rukshana Mohamad-Ramshan / Laura C McGary / ...Authors: Philip Barbulescu / Chetan K Chana / Matthew K Wong / Ines Ben Makhlouf / Jeffrey P Bruce / Yuqing Feng / Alexander F A Keszei / Cassandra Wong / Rukshana Mohamad-Ramshan / Laura C McGary / Mohammad A Kashem / Derek F Ceccarelli / Stephen Orlicky / Yifei Fang / Huihui Kuang / Mohammad Mazhab-Jafari / Rossanna C Pezo / Ashok S Bhagwat / Trevor J Pugh / Anne-Claude Gingras / Frank Sicheri / Alberto Martin /
Abstract: A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic ...A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2). However, FAM72A downregulates UNG2 permitting dUs to persist and trigger SHM and CSR. How FAM72A promotes UNG2 degradation is unknown. Here, we show that FAM72A recruits a C-terminal to LisH (CTLH) E3 ligase complex to target UNG2 for proteasomal degradation. Deficiency in CTLH complex components result in elevated UNG2 and reduced SHM and CSR. Cryo-EM structural analysis reveals FAM72A directly binds to MKLN1 within the CTLH complex to recruit and ubiquitinate UNG2. Our study further suggests that FAM72A hijacks the CTLH complex to promote mutagenesis in cancer. These findings show that FAM72A is an E3 ligase substrate adaptor critical for humoral immunity and cancer development.
History
DepositionAug 14, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 11, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Muskelin
B: Muskelin


Theoretical massNumber of molelcules
Total (without water)174,4042
Polymers174,4042
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 Muskelin


Mass: 87202.195 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MKLN1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UL63

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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: Cryo-EM structure of the inner MKLN1 dimer from an autoinhibited MKLN1 tetramer
Type: COMPLEX / Details: From focused refinement of MKLN1 tetramer / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 57.08 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 159095 / Symmetry type: POINT
Atomic model buildingB value: 168.75
Atomic model building
ID 3D fitting-IDAccession codeChain-IDInitial refinement model-IDSource nameType
11Q9UL63A1AlphaFoldin silico model
21Q9UL63B1AlphaFoldin silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0019503
ELECTRON MICROSCOPYf_angle_d0.38712887
ELECTRON MICROSCOPYf_dihedral_angle_d2.6191292
ELECTRON MICROSCOPYf_chiral_restr0.0381383
ELECTRON MICROSCOPYf_plane_restr0.0021675

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