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- PDB-8s5a: The crystal structure of FAN1 Nuclease bound to 5' phosphorylated... -

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Basic information

Entry
Database: PDB / ID: 8s5a
TitleThe crystal structure of FAN1 Nuclease bound to 5' phosphorylated p(dG)/3'(dT-dT-dT-dT) double flap DNA
Components
  • DNA (5'-D(*AP*AP*CP*AP*CP*GP*CP*CP*TP*AP*GP*AP*CP*TP*CP*CP*TP*CP*A)-3')
  • DNA (5'-D(*TP*TP*TP*GP*AP*GP*GP*AP*GP*TP*CP*TP*T)-3')
  • DNA (5'-D(P*GP*AP*GP*GP*CP*GP*TP*G)-3')
  • Fanconi-associated nuclease 1
KeywordsDNA / nuclease FAN1
Function / homology
Function and homology information


flap-structured DNA binding / phosphodiesterase I / 5'-flap endonuclease activity / Hydrolases; Acting on ester bonds; Endodeoxyribonucleases producing 5'-phosphomonoesters / ubiquitin-modified protein reader activity / 5'-3' exonuclease activity / phosphodiesterase I activity / interstrand cross-link repair / intercellular bridge / nucleotide-excision repair ...flap-structured DNA binding / phosphodiesterase I / 5'-flap endonuclease activity / Hydrolases; Acting on ester bonds; Endodeoxyribonucleases producing 5'-phosphomonoesters / ubiquitin-modified protein reader activity / 5'-3' exonuclease activity / phosphodiesterase I activity / interstrand cross-link repair / intercellular bridge / nucleotide-excision repair / Fanconi Anemia Pathway / double-strand break repair via homologous recombination / cilium / DNA repair / magnesium ion binding / zinc ion binding / nucleoplasm / nucleus / cytosol
Similarity search - Function
: / : / : / Fanconi-associated nuclease 1, SAP subdomain / Fanconi-associated nuclease 1, TPR domain / Fanconi-associated nuclease 1-like / : / FAN1, HTH domain / VRR-NUC domain / VRR-NUC domain ...: / : / : / Fanconi-associated nuclease 1, SAP subdomain / Fanconi-associated nuclease 1, TPR domain / Fanconi-associated nuclease 1-like / : / FAN1, HTH domain / VRR-NUC domain / VRR-NUC domain / VRR_NUC / Rad18-like CCHC zinc finger / tRNA endonuclease-like domain superfamily / Rad18, zinc finger UBZ4-type / Zinc finger UBZ4-type profile.
Similarity search - Domain/homology
DNA / DNA (> 10) / Fanconi-associated nuclease 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.645 Å
AuthorsCostanzi, E. / Thomsen, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: A FAN1 point mutation associated with accelerated Huntington's disease progression alters its PCNA-mediated assembly on DNA.
Authors: Jonas Aretz / Gayathri Jeyasankar / Anna Salerno-Kochan / Maren Thomsen / Gabriel Thieulin-Pardo / Tasir Haque / Edith Monteagudo / Dan Felsenfeld / Michael Finley / Thomas F Vogt / Julien ...Authors: Jonas Aretz / Gayathri Jeyasankar / Anna Salerno-Kochan / Maren Thomsen / Gabriel Thieulin-Pardo / Tasir Haque / Edith Monteagudo / Dan Felsenfeld / Michael Finley / Thomas F Vogt / Julien Boudet / Brinda C Prasad /
Abstract: FAN1 is an endo- and exo-nuclease involved in DNA and interstrand crosslink repair. Genome-wide association studies of people with Huntington's disease revealed a strong association between the FAN1 ...FAN1 is an endo- and exo-nuclease involved in DNA and interstrand crosslink repair. Genome-wide association studies of people with Huntington's disease revealed a strong association between the FAN1 R507H mutation and early disease onset, however the underlying mechanism(s) remains unclear. FAN1 has previously been implicated in modulating triplet repeat expansion in a PCNA dependent manner. To examine the role of PCNA on FAN1 activation, we solved the cryo-EM structures of a PCNA-FAN1-DNA complex. Our findings reveal that the FAN1 R507 residue directly interacts with PCNA D232. Biophysical interaction studies demonstrated that FAN1 enhances the binding affinity of PCNA for DNA, a synergistic effect disrupted in mutants carrying the R507H mutation. In contrast, PCNA does not affect the affinity of FAN1 for DNA but does modulate FAN1 activity upon ternary complex formation. The weakened and functionally altered FAN1 R507H-PCNA-DNA complex may partly impair the FAN1-mediated repair of CAG extrahelical extrusions, providing a potential explanation for the mutation's role in accelerating disease progression.
History
DepositionFeb 23, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 5, 2025Provider: repository / Type: Initial release
Revision 1.1Jun 4, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fanconi-associated nuclease 1
B: DNA (5'-D(*AP*AP*CP*AP*CP*GP*CP*CP*TP*AP*GP*AP*CP*TP*CP*CP*TP*CP*A)-3')
C: DNA (5'-D(P*GP*AP*GP*GP*CP*GP*TP*G)-3')
D: DNA (5'-D(*TP*TP*TP*GP*AP*GP*GP*AP*GP*TP*CP*TP*T)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,4297
Polymers87,3144
Non-polymers1163
Water28816
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4690 Å2
ΔGint-76 kcal/mol
Surface area34230 Å2
Unit cell
Length a, b, c (Å)91.626, 100.547, 112.879
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Fanconi-associated nuclease 1 / FANCD2/FANCI-associated nuclease 1 / hFAN1 / Myotubularin-related protein 15


Mass: 74162.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FAN1, KIAA1018, MTMR15 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9Y2M0, Hydrolases; Acting on ester bonds; Endodeoxyribonucleases producing 5'-phosphomonoesters, phosphodiesterase I

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DNA chain , 3 types, 3 molecules BCD

#2: DNA chain DNA (5'-D(*AP*AP*CP*AP*CP*GP*CP*CP*TP*AP*GP*AP*CP*TP*CP*CP*TP*CP*A)-3')


Mass: 5718.727 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: DNA chain DNA (5'-D(P*GP*AP*GP*GP*CP*GP*TP*G)-3')


Mass: 2507.653 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: DNA chain DNA (5'-D(*TP*TP*TP*GP*AP*GP*GP*AP*GP*TP*CP*TP*T)-3')


Mass: 4925.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 3 types, 19 molecules

#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.01 Å3/Da / Density % sol: 59.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.1 M Hepes/MOPS pH: 7.25, 0.1M Sodium formate 0.1M Ammonium acetate 0.1M Sodium citrate tribasic dihydrate 0.1M Potassium sodium tartrate tetrahydrate 0.1M Sodium oxamate 21% v/v Ethylene ...Details: 0.1 M Hepes/MOPS pH: 7.25, 0.1M Sodium formate 0.1M Ammonium acetate 0.1M Sodium citrate tribasic dihydrate 0.1M Potassium sodium tartrate tetrahydrate 0.1M Sodium oxamate 21% v/v Ethylene glycol 21 % w/v PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: May 27, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.645→43.395 Å / Num. obs: 31091 / % possible obs: 99.9 % / Redundancy: 11.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.071 / Net I/σ(I): 16.6
Reflection shellResolution: 2.645→2.691 Å / Num. unique obs: 1538 / CC1/2: 0.845

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
autoPROCdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.645→43.395 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.925 / WRfactor Rfree: 0.288 / WRfactor Rwork: 0.241 / SU B: 15.89 / SU ML: 0.314 / Average fsc free: 0.8331 / Average fsc work: 0.8521 / Cross valid method: FREE R-VALUE / ESU R: 0.502 / ESU R Free: 0.309
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2731 823 2.647 %
Rwork0.2343 30267 -
all0.235 --
obs-31090 99.849 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 84.729 Å2
Baniso -1Baniso -2Baniso -3
1--6.12 Å20 Å2-0 Å2
2--8.218 Å20 Å2
3----2.099 Å2
Refinement stepCycle: LAST / Resolution: 2.645→43.395 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4785 816 3 16 5620
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0125630
X-RAY DIFFRACTIONr_bond_other_d0.0020.0174918
X-RAY DIFFRACTIONr_angle_refined_deg1.2491.5467803
X-RAY DIFFRACTIONr_angle_other_deg1.1791.70411259
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1795587
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.26321.24242
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.91915769
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3671535
X-RAY DIFFRACTIONr_chiral_restr0.0550.2735
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025794
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021317
X-RAY DIFFRACTIONr_nbd_refined0.1590.21041
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1510.24448
X-RAY DIFFRACTIONr_nbtor_refined0.1590.22524
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0730.22300
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1070.2106
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0020.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.0310.28
X-RAY DIFFRACTIONr_nbd_other0.1610.219
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.0830.23
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.020.21
X-RAY DIFFRACTIONr_mcbond_it3.7679.3162364
X-RAY DIFFRACTIONr_mcbond_other3.7579.3142363
X-RAY DIFFRACTIONr_mcangle_it5.82113.9632945
X-RAY DIFFRACTIONr_mcangle_other5.8213.9652946
X-RAY DIFFRACTIONr_scbond_it3.4479.5043266
X-RAY DIFFRACTIONr_scbond_other3.4479.5013265
X-RAY DIFFRACTIONr_scangle_it5.43514.2254858
X-RAY DIFFRACTIONr_scangle_other5.43514.2274859
X-RAY DIFFRACTIONr_lrange_it7.983103.7186325
X-RAY DIFFRACTIONr_lrange_other7.981103.7166324
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.645-2.7140.36550.3812219X-RAY DIFFRACTION99.8682
2.714-2.7880.317560.3852138X-RAY DIFFRACTION99.7726
2.788-2.8690.365590.3422081X-RAY DIFFRACTION99.7669
2.869-2.9570.391430.3142062X-RAY DIFFRACTION99.763
2.957-3.0540.419510.3041954X-RAY DIFFRACTION99.8506
3.054-3.1610.312510.2961925X-RAY DIFFRACTION99.8484
3.161-3.280.273500.2751826X-RAY DIFFRACTION100
3.28-3.4130.34480.2481782X-RAY DIFFRACTION99.9454
3.413-3.5650.313310.2561723X-RAY DIFFRACTION100
3.565-3.7380.273590.2551622X-RAY DIFFRACTION99.9405
3.738-3.940.32460.2341563X-RAY DIFFRACTION100
3.94-4.1780.279460.2031491X-RAY DIFFRACTION100
4.178-4.4660.243430.191368X-RAY DIFFRACTION100
4.466-4.8220.237420.1911314X-RAY DIFFRACTION100
4.822-5.280.211320.1941214X-RAY DIFFRACTION100
5.28-5.90.31260.2261108X-RAY DIFFRACTION100
5.9-6.8060.337280.266978X-RAY DIFFRACTION100
6.806-8.3180.216300.22834X-RAY DIFFRACTION99.7691
8.318-11.6920.214200.166669X-RAY DIFFRACTION99.7106
11.692-43.3950.27770.281396X-RAY DIFFRACTION95.9524

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