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- EMDB-53229: Human myoferlin (1-1997) in the lipid-free, Ca2+-bound state -

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Basic information

Entry
Database: EMDB / ID: EMD-53229
TitleHuman myoferlin (1-1997) in the lipid-free, Ca2+-bound state
Map data
Sample
  • Complex: Lipid-free human myoferlin (residues 1-1997) in the Ca2+-bound state
    • Protein or peptide: Myoferlin
  • Ligand: CALCIUM ION
KeywordsFerlins / myoferlin / multi-C2 domain / 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: 3.2 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 21, 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_53229.png

Downloads & links

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Map

FileDownload / File: emd_53229.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.72 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.27775857 - 0.4126869
Average (Standard dev.)-0.00027874543 (±0.00881285)
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_53229_msk_1.map
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Additional map: #1

Fileemd_53229_additional_1.map
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Half map: #1

Fileemd_53229_half_map_1.map
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Half map: #2

Fileemd_53229_half_map_2.map
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Sample components

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Entire : Lipid-free human myoferlin (residues 1-1997) in the Ca2+-bound state

EntireName: Lipid-free human myoferlin (residues 1-1997) in the Ca2+-bound state
Components
  • Complex: Lipid-free human myoferlin (residues 1-1997) in the Ca2+-bound state
    • Protein or peptide: Myoferlin
  • Ligand: CALCIUM ION

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Supramolecule #1: Lipid-free human myoferlin (residues 1-1997) in the Ca2+-bound state

SupramoleculeName: Lipid-free human myoferlin (residues 1-1997) in the Ca2+-bound state
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: Cytosolic domain of human myoferlin (residues 1-1997), cloned in-frame with an N-terminal twin-StrepII 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: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 2 / Number of copies: 6 / 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

Concentration1.15 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
25.0 mMHEPES4-(2-Hydroxyethyl)-1-piperazine ethanesulfonic acid
200.0 mMKClpotassium chloride
2.5 % (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
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
Details: After the application of 3 uL sample (A280~1.15), the grids were blotted for 7-7.5s at a blot force of 3..
DetailsPrior to cryo-EM grid preparation, human myoferlin (1-1997) was subjected to GraFix in the presence of 0.5 mM CaCl2. GraFix fractions were quenched with 50 mM Lysine and Arginine, buffer exchanged and concentrated to A280~1.15

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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: 2 / Number real images: 19413 / Average exposure time: 3.42 sec. / Average electron dose: 39.91 e/Å2
Details: Dataset 1: 10373 movies, 10354 movies were accepted after curation, total fluence on sample: 39.91 e-/A2 (3.42s per exposure). Dataset 2: 9040 movies, 8669 movies were accepted after ...Details: Dataset 1: 10373 movies, 10354 movies were accepted after curation, total fluence on sample: 39.91 e-/A2 (3.42s per exposure). Dataset 2: 9040 movies, 8669 movies were accepted after curation, total fluence on sample: 39.85 e-/A2 (3.69s per exposure).
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: 2.3000000000000003 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: 9109366
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: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v.4.5) / Number images used: 102339
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: 1 / Software - Name: cryoSPARC (ver. v.4.5)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Chain ID: E / Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
SoftwareName: UCSF ChimeraX (ver. v.1.8)
RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 174.4
Output model

PDB-9qln:
Human myoferlin (1-1997) in the lipid-free, Ca2+-bound state

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