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- EMDB-44348: Cryo-EM structure of human dysferlin monomer -

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Basic information

Entry
Database: EMDB / ID: EMD-44348
TitleCryo-EM structure of human dysferlin monomer
Map data
Sample
  • Organelle or cellular component: Dysferlin monomer
    • Protein or peptide: Dysferlin
KeywordsSingle-pass type II membrane protein / membrane repair / calcium ion sensor / MEMBRANE PROTEIN
Function / homology
Function and homology information


monocyte activation involved in immune response / regulation of neurotransmitter secretion / calcium-dependent phospholipid binding / macrophage activation involved in immune response / negative regulation of phagocytosis / endocytic vesicle / Smooth Muscle Contraction / T-tubule / cytoplasmic vesicle membrane / sarcolemma ...monocyte activation involved in immune response / regulation of neurotransmitter secretion / calcium-dependent phospholipid binding / macrophage activation involved in immune response / negative regulation of phagocytosis / endocytic vesicle / Smooth Muscle Contraction / T-tubule / cytoplasmic vesicle membrane / sarcolemma / phospholipid binding / centriolar satellite / synaptic vesicle membrane / late endosome / early endosome / endosome / 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 speciesunidentified (others) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.96 Å
AuthorsHuang HL / Heissler SM / Chinthalapudi K
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Cryo-EM structures of the membrane repair protein dysferlin.
Authors: Hsiang-Ling Huang / Giovanna Grandinetti / Sarah M Heissler / Krishna Chinthalapudi /
Abstract: Plasma membrane repair in response to damage is essential for cell viability. The ferlin family protein dysferlin plays a key role in Ca-dependent membrane repair in striated muscles. Mutations in ...Plasma membrane repair in response to damage is essential for cell viability. The ferlin family protein dysferlin plays a key role in Ca-dependent membrane repair in striated muscles. Mutations in dysferlin lead to a spectrum of diseases known as dysferlinopathies. The lack of a structure of dysferlin and other ferlin family members has impeded a mechanistic understanding of membrane repair mechanisms and the development of therapies. Here, we present the cryo-EM structures of the full-length human dysferlin monomer and homodimer at 2.96 Å and 4.65 Å resolution. These structures define the architecture of dysferlin, ferlin family-specific domains, and homodimerization mechanisms essential to function. Furthermore, biophysical and cell biology studies revealed how missense mutations in dysferlin contribute to disease mechanisms. In summary, our study provides a framework for the molecular mechanisms of dysferlin and the broader ferlin family, offering a foundation for the development of therapeutic strategies aimed at treating dysferlinopathies.
History
DepositionMar 30, 2024-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateNov 27, 2024-
Current statusNov 27, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44348.png

Downloads & links

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Map

FileDownload / File: emd_44348.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.89 Å/pix.
x 512 pix.
= 456.192 Å		0.89 Å/pix.
x 512 pix.
= 456.192 Å		0.89 Å/pix.
x 512 pix.
= 456.192 Å

Surface

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.891 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0639
Minimum - Maximum-0.044756338 - 1.9496363
Average (Standard dev.)0.000434392 (±0.012659329)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 456.192 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_44348_msk_1.map
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Half map: #2

Fileemd_44348_half_map_1.map
Projections & Slices
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Histogram

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Half map: #1

Fileemd_44348_half_map_2.map
Projections & Slices
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Sample components

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Entire : Dysferlin monomer

EntireName: Dysferlin monomer
Components
  • Organelle or cellular component: Dysferlin monomer
    • Protein or peptide: Dysferlin

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Supramolecule #1: Dysferlin monomer

SupramoleculeName: Dysferlin monomer / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: unidentified (others)
Molecular weightTheoretical: 237.295 KDa

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Macromolecule #1: Dysferlin

MacromoleculeName: Dysferlin / type: protein_or_peptide / ID: 1 / Details: Strep tag is cleaved from the C-terminus / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 237.577094 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MLRVFILYAE NVHTPDTDIS DAYCSAVFAG VKKRTKVIKN SVNPVWNEGF EWDLKGIPLD QGSELHVVVK DHETMGRNRF LGEAKVPLR EVLATPSLSA SFNAPLLDTK KQPTGASLVL QVSYTPLPGA VPLFPPPTPL EPSPTLPDLD VVADTGGEED T EDQGLTGD ...String:
MLRVFILYAE NVHTPDTDIS DAYCSAVFAG VKKRTKVIKN SVNPVWNEGF EWDLKGIPLD QGSELHVVVK DHETMGRNRF LGEAKVPLR EVLATPSLSA SFNAPLLDTK KQPTGASLVL QVSYTPLPGA VPLFPPPTPL EPSPTLPDLD VVADTGGEED T EDQGLTGD EAEPFLDQSG GPGAPTTPRK LPSRPPPHYP GIKRKRSAPT SRKLLSDKPQ DFQIRVQVIE GRQLPGVNIK PV VKVTAAG QTKRTRIHKG NSPLFNETLF FNLFDSPGEL FDEPIFITVV DSRSLRTDAL LGEFRMDVGT IYREPRHAYL RKW LLLSDP DDFSAGARGY LKTSLCVLGP GDEAPLERKD PSEDKEDIES NLLRPTGVAL RGAHFCLKVF RAEDLPQMDD AVMD NVKQI FGFESNKKNL VDPFVEVSFA GKMLCSKILE KTANPQWNQN ITLPAMFPSM CEKMRIRIID WDRLTHNDIV ATTYL SMSK ISAPGGEIEE EPAGAVKPSK ASDLDDYLGF LPTFGPCYIN LYGSPREFTG FPDPYTELNT GKGEGVAYRG RLLLSL ETK LVEHSEQKVE DLPADDILRV EKYLRRRKYS LFAAFYSATM LQDVDDAIQF EVSIGNYGNK FDMTCLPLAS TTQYSRA VF DGCHYYYLPW GNVKPVVVLS SYWEDISHRI ETQNQLLGIA DRLEAGLEQV HLALKAQCST EDVDSLVAQL TDELIAGC S QPLGDIHETP SATHLDQYLY QLRTHHLSQI TEAALALKLG HSELPAALEQ AEDWLLRLRA LAEEPQNSLP DIVIWMLQG DKRVAYQRVP AHQVLFSRRG ANYCGKNCGK LQTIFLKYPM EKVPGARMPV QIRVKLWFGL SVDEKEFNQF AEGKLSVFAE TYENETKLA LVGNWGTTGL TYPKFSDVTG KIKLPKDSFR PSAGWTWAGD WFVCPEKTLL HDMDAGHLSF VEEVFENQTR L PGGQWIYM SDNYTDVNGE KVLPKDDIEC PLGWKWEDEE WSTDLNRAVD EQGWEYSITI PPERKPKHWV PAEKMYYTHR RR RWVRLRR RDLSQMEALK RHRQAEAEGE GWEYASLFGW KFHLEYRKTD AFRRRRWRRR MEPLEKTGPA AVFALEGALG GVM DDKSED SMSVSTLSFG VNRPTISCIF DYGNRYHLRC YMYQARDLAA MDKDSFSDPY AIVSFLHQSQ KTVVVKNTLN PTWD QTLIF YEIEIFGEPA TVAEQPPSIV VELYDHDTYG ADEFMGRCIC QPSLERMPRL AWFPLTRGSQ PSGELLASFE LIQRE KPAI HHIPGFEVQE TSRILDESED TDLPYPPPQR EANIYMVPQN IKPALQRTAI EILAWGLRNM KSYQLANISS PSLVVE CGG QTVQSCVIRN LRKNPNFDIC TLFMEVMLPR EELYCPPITV KVIDNRQFGR RPVVGQCTIR SLESFLCDPY SAESPSP QG GPDDVSLLSP GEDVLIDIDD KEPLIPIQEE EFIDWWSKFF ASIGEREKCG SYLEKDFDTL KVYDTQLENV EAFEGLSD F CNTFKLYRGK TQEETEDPSV IGEFKGLFKI YPLPEDPAIP MPPRQFHQLA AQGPQECLVR IYIVRAFGLQ PKDPNGKCD PYIKISIGKK SVSDQDNYIP CTLEPVFGKM FELTCTLPLE KDLKITLYDY DLLSKDEKIG ETVVDLENRL LSKFGARCGL PQTYCVSGP NQWRDQLRPS QLLHLFCQQH RVKAPVYRTD RVMFQDKEYS IEEIEAGRIP NPHLGPVEER LALHVLQQQG L VPEHVESR PLYSPLQPDI EQGKLQMWVD LFPKALGRPG PPFNITPRRA RRFFLRCIIW NTRDVILDDL SLTGEKMSDI YV KGWMIGF EEHKQKTDVH YRSLGGEGNF NWRFIFPFDY LPAEQVCTIA KKDAFWRLDK TESKIPARVV FQIWDNDKFS FDD FLGSLQ LDLNRMPKPA KTAKKCSLDQ LDDAFHPEWF VSLFEQKTVK GWWPCVAEEG EKKILAGKLE MTLEIVAESE HEER PAGQG RDEPNMNPKL EDPRRPDTSF LWFTSPYKTM KFILWRRFRW AIILFIILFI LLLFLAIFIY AFPNYAAMKL VKPFS

UniProtKB: Dysferlin

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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: 7.4
GridModel: UltrAuFoil / Support film - Material: GOLD
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN 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: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.96 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 271263
Initial angle assignmentType: NOT APPLICABLE / Software - Name: cryoSPARC
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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