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- EMDB-53222: Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc... -

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Entry
Database: EMDB / ID: EMD-53222
TitleHuman myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc (15 mol% DOPS, 5 mol% Cholesterol)
Map datahuman myoferlin (1-1997)-MSP2N2 complex (15 mol% DOPS, 5 mol% Cholesterol), map M5 (consensus map)
Sample
  • Complex: Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc (comprising 15 mol% DOPS, 5 mol% Cholesterol)
    • Protein or peptide: Myoferlin
  • Ligand: 1,2-DICAPROYL-SN-PHOSPHATIDYL-L-SERINE
  • Ligand: CALCIUM ION
KeywordsFerlins / myoferlin / multi-C2 domains / lipid nanodisc / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of neurotransmitter secretion / plasma membrane repair / blood circulation / muscle contraction / caveola / phospholipid binding / centriolar satellite / synaptic vesicle membrane / nuclear envelope / cytoplasmic vesicle ...regulation of neurotransmitter secretion / plasma membrane repair / blood circulation / muscle contraction / caveola / phospholipid binding / centriolar satellite / synaptic vesicle membrane / nuclear envelope / cytoplasmic vesicle / nuclear membrane / ciliary basal body / cilium / intracellular membrane-bounded organelle / calcium ion binding / extracellular exosome / plasma membrane
Similarity search - Function
Ferlin A-domain / FerA (NUC095) domain / FerA / Ferlin B-domain / FerIin domain / Ferlin, C-terminal domain / Ferlin, second C2 domain / Ferlin family / Ferlin, third C2 domain / Ferlin, fourth C2 domain ...Ferlin A-domain / FerA (NUC095) domain / FerA / Ferlin B-domain / FerIin domain / Ferlin, C-terminal domain / Ferlin, second C2 domain / Ferlin family / Ferlin, third C2 domain / Ferlin, fourth C2 domain / Ferlin, fifth C2 domain / Ferlin, sixth C2 domain / Ferlin, first C2 domain / : / FerB (NUC096) domain / FerI (NUC094) domain / Ferlin C-terminus / Ferlin dsRNA-binding domain-like domain / FerB / FerI / Peroxin/Ferlin domain / Dysferlin domain, N-terminal region. / Dysferlin domain, C-terminal region. / Protein kinase C conserved region 2 (CalB) / C2 domain / C2 domain / C2 domain profile. / C2 domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.74 Å
AuthorsCretu C / Moser T
Funding support Germany, 1 items
OrganizationGrant numberCountry
German Research Foundation (DFG)CR 937/2-1 and EXC 2067/1-390729940 Germany
CitationJournal: EMBO J / Year: 2025
Title: Structural insights into lipid membrane binding by human ferlins.
Authors: Constantin Cretu / Aleksandar Chernev / Csaba Zoltán Kibédi Szabó / Vladimir Pena / Henning Urlaub / Tobias Moser / Julia Preobraschenski /
Abstract: Ferlins are ancient membrane proteins with a unique architecture, and play central roles in crucial processes that involve Ca-dependent vesicle fusion. Despite their links to multiple human diseases ...Ferlins are ancient membrane proteins with a unique architecture, and play central roles in crucial processes that involve Ca-dependent vesicle fusion. Despite their links to multiple human diseases and numerous functional studies, a mechanistic understanding of how these multi-C domain-containing proteins interact with lipid membranes to promote membrane remodelling and fusion is currently lacking. Here we obtain near-complete cryo-electron microscopy structures of human myoferlin and dysferlin in their Ca- and lipid-bound states. We show that ferlins adopt compact, ring-like tertiary structures upon membrane binding. The top arch of the ferlin ring, composed of the CC-CD region, is rigid and exhibits only little variability across the observed functional states. In contrast, the N-terminal CB and the C-terminal CF-CG domains cycle between alternative conformations and, in response to Ca, close the ferlin ring, promoting tight interaction with the target membrane. Probing key domain interfaces validates the observed architecture, and informs a model of how ferlins engage lipid bilayers in a Ca-dependent manner. This work reveals the general principles of human ferlin structures and provides a framework for future analyses of ferlin-dependent cellular functions and disease mechanisms.
History
DepositionMar 20, 2025-
Header (metadata) releaseJun 4, 2025-
Map releaseJun 4, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_53222.png

Downloads & links

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Map

FileDownload / File: emd_53222.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationhuman myoferlin (1-1997)-MSP2N2 complex (15 mol% DOPS, 5 mol% Cholesterol), map M5 (consensus map)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.72 Å/pix.
x 360 pix.
= 259.2 Å		0.72 Å/pix.
x 360 pix.
= 259.2 Å		0.72 Å/pix.
x 360 pix.
= 259.2 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.72 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.016
Minimum - Maximum-0.08280086 - 0.17743005
Average (Standard dev.)-0.0000087921835 (±0.0043174964)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 259.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_53222_msk_1.map
Projections & Slices
AxesZYX

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Additional map: human myoferlin (1-1997)-MSP2N2 complex (15 mol% DOPS, 5...

Fileemd_53222_additional_1.map
Annotationhuman myoferlin (1-1997)-MSP2N2 complex (15 mol% DOPS, 5 mol% Cholesterol), overall map (map M6)
Projections & Slices
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Half map: human myoferlin (1-1997)-MSP2N2 complex (15 mol% DOPS, 5...

Fileemd_53222_half_map_1.map
Annotationhuman myoferlin (1-1997)-MSP2N2 complex (15 mol% DOPS, 5 mol% Cholesterol), half map A (map M5, consensus map)
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: human myoferlin (1-1997)-MSP2N2 complex (15 mol% DOPS, 5...

Fileemd_53222_half_map_2.map
Annotationhuman myoferlin (1-1997)-MSP2N2 complex (15 mol% DOPS, 5 mol% Cholesterol), half map B (map M5, consensus map)
Projections & Slices
AxesZYX

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Sample components

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Entire : Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc...

EntireName: Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc (comprising 15 mol% DOPS, 5 mol% Cholesterol)
Components
  • Complex: Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc (comprising 15 mol% DOPS, 5 mol% Cholesterol)
    • Protein or peptide: Myoferlin
  • Ligand: 1,2-DICAPROYL-SN-PHOSPHATIDYL-L-SERINE
  • Ligand: CALCIUM ION

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Supramolecule #1: Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc...

SupramoleculeName: Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc (comprising 15 mol% DOPS, 5 mol% Cholesterol)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Myoferlin

MacromoleculeName: Myoferlin / type: protein_or_peptide / ID: 1
Details: The cytosolic domain of human myoferlin (residues 1-1997), cloned in-frame with a twin-StrepII affinity tag.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 232.625953 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MASWSHPQFE KGGGSGGGSG GGSWSHPQFE KLEVLFQGPG SGDKDCEQSN AMLRVIVESA SNIPKTKFGK PDPIVSVIFK DEKKKTKKV DNELNPVWNE ILEFDLRGIP LDFSSSLGII VKDFETIGQN KLIGTATVAL KDLTGDQSRS LPYKLISLLN E RGQDTGAT ...String:
MASWSHPQFE KGGGSGGGSG GGSWSHPQFE KLEVLFQGPG SGDKDCEQSN AMLRVIVESA SNIPKTKFGK PDPIVSVIFK DEKKKTKKV DNELNPVWNE ILEFDLRGIP LDFSSSLGII VKDFETIGQN KLIGTATVAL KDLTGDQSRS LPYKLISLLN E RGQDTGAT IDLVIGYDPP SAPHPNDLSG PSVPGMGGDG EEDEGDEDRL DNAVRGPGPK GPVGTVSEAQ LARRLTKVKN SR RMLSNKP QDFQIRVRVI EGRQLSGNNI RPVVKVHVCG QTHRTRIKRG NNPFFDELFF YNVNMTPSEL MDEIISIRVY NSH SLRADC LMGEFKIDVG FVYDEPGHAV MRKWLLLNDP EDTSSGSKGY MKVSMFVLGT GDEPPPERRD RDNDSDDVES NLLL PAGIA LRWVTFLLKI YRAEDIPQMD DAFSQTVKEI FGGNADKKNL VDPFVEVSFA GKKVCTNIIE KNANPEWNQV VNLQI KFPS VCEKIKLTIY DWDRLTKNDV VGTTYLHLSK IAASGGEVED FSSSGTGAAS YTVNTGETEV GFVPTFGPCY LNLYGS PRE YTGFPDPYDE LNTGKGEGVA YRGRILVELA TFLEKTPPDK KLEPISNDDL LVVEKYQRRR KYSLSAVFHS ATMLQDV GE AIQFEVSIGN YGNRFDTTCK PLASTTQYSR AVFDGNYYYY LPWAHTKPVV TLTSYWEDIS HRLDAVNTLL AMAERLQT N IEALKSGIQG KIPANQLAEL WLKLIDEVIE DTRYTLPLTE GKANVTVLDT QIRKLRSRSL SQIHEAAVRM RSEATDVKS TLAEIEDWLD KLMQLTEEPQ NSMPDIIIWM IRGEKRLAYA RIPAHQVLYS TSGENASGKY CGKTQTIFLK YPQEKNNGPK VPVELRVNI WLGLSAVEKK FNSFAEGTFT VFAEMYENQA LMFGKWGTSG LVGRHKFSDV TGKIKLKREF FLPPKGWEWE G EWIVDPER SLLTEADAGH TEFTDEVYQN ESRYPGGDWK PAEDTYTDAN GDKAASPSEL TCPPGWEWED DAWSYDINRA VD EKGWEYG ITIPPDHKPK SWVAAEKMYH THRRRRLVRK RKKDLTQTAS STARAMEELQ DQEGWEYASL IGWKFHWKQR SSD TFRRRR WRRKMAPSET HGAAAIFKLE GALGADTTED GDEKSLEKQK HSATTVFGAN TPIVSCNFDR VYIYHLRCYV YQAR NLLAL DKDSFSDPYA HICFLHRSKT TEIIHSTLNP TWDQTIIFDE VEIYGEPQTV LQNPPKVIME LFDNDQVGKD EFLGR SIFS PVVKLNSEMD ITPKLLWHPV MNGDKACGDV LVTAELILRG KDGSNLPILP PQRAPNLYMV PQGIRPVVQL TAIEIL AWG LRNMKNFQMA SITSPSLVVE CGGERVESVV IKNLKKTPNF PSSVLFMKVF LPKEELYMPP LVIKVIDHRQ FGRKPVV GQ CTIERLDRFR CDPYAGKEDI VPQLKASLLS APPCRDIVIE MEDTKPLLAS KLTEKEEEIV DWWSKFYASS GEHEKCGQ Y IQKGYSKLKI YNCELENVAE FEGLTDFSDT FKLYRGKSDE NEDPSVVGEF KGSFRIYPLP DDPSVPAPPR QFRELPDSV PQECTVRIYI VRGLELQPQD NNGLCDPYIK ITLGKKVIED RDHYIPNTLN PVFGRMYELS CYLPQEKDLK ISVYDYDTFT RDEKVGETI IDLENRFLSR FGSHCGIPEE YCVSGVNTWR DQLRPTQLLQ NVARFKGFPQ PILSEDGSRI RYGGRDYSLD E FEANKILH QHLGAPEERL ALHILRTQGL VPEHVETRTL HSTFQPNISQ GKLQMWVDVF PKSLGPPGPP FNITPRKAKK YY LRVIIWN TKDVILDEKS ITGEEMSDIY VKGWVPGNEE NKQKTDVHYR SLDGEGNFNW RFVFPFDYLP AEQLCIVAKK EHF WSIDQT EFRIPPRLII QIWDNDKFSL DDYLGFLELD LRHTIIPAKS PEKCRLDMIP DLKAMNPLKA KTASLFEQKS MKGW WPCYA EKDGARVMAG KVEMTLEILN EKEADERPAG KGRDEPNMNP KLD

UniProtKB: Myoferlin

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Macromolecule #2: 1,2-DICAPROYL-SN-PHOSPHATIDYL-L-SERINE

MacromoleculeName: 1,2-DICAPROYL-SN-PHOSPHATIDYL-L-SERINE / type: ligand / ID: 2 / Number of copies: 2 / Formula: PSF
Molecular weightTheoretical: 455.437 Da
Chemical component information

ChemComp-PSF:
1,2-DICAPROYL-SN-PHOSPHATIDYL-L-SERINE

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Macromolecule #3: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 10 / Formula: CA
Molecular weightTheoretical: 40.078 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

Concentration0.77 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
25.0 mMHEPES4-(2-Hydroxyethyl)-1-piperazine ethanesulfonic acid
200.0 mMKClpotassium chloride
1.25 % (v/v)C3H8O3glycerol
1.0 mMTCEPTris(2-carboxyethyl)phosphine hydrochloride
0.5 mMCaCl2calcium chloride
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
Details: The grid was treated with the Plasma Cleaner (Harrick Plasma) for 1 min at medium settings, followed by vitrification in liquid ethane-propane (37%/63%), cooled by liquid nitrogen
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
DetailsPrior to cryo-EM grid preparation, the sample was crosslinked with glutaraldehyde (0.05 % (v/v)) in batch and purified by size-exclusion chromatography

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV
SoftwareName: EPU (ver. v.3.6)
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 9800 / Average exposure time: 3.45 sec. / Average electron dose: 39.85 e/Å2 / Details: 9621 movies were accepted after curation
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2917286
CTF correctionSoftware - Name: cryoSPARC (ver. v.4.5) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab initio reconstruction (in cryoSPARC)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v.4.5) / Number images used: 277729
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v.4.5)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v.4.5)
Final 3D classificationNumber classes: 5 / Software - Name: RELION (ver. v.5.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 135.43
Output model

PDB-9qkv:
Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc (15 mol% DOPS, 5 mol% Cholesterol)

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