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- PDB-9b8k: Cryo-EM structure of human dysferlin monomer -

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Basic information

Entry
Database: PDB / ID: 9b8k
TitleCryo-EM structure of human dysferlin monomer
ComponentsDysferlin
KeywordsMEMBRANE PROTEIN / Single-pass type II membrane protein / membrane repair / calcium ion sensor
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 speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.96 Å
AuthorsHuang, H.L. / Heissler, S.M. / Chinthalapudi, K.
Funding support1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dysferlin


Theoretical massNumber of molelcules
Total (without water)237,5771
Polymers237,5771
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 Dysferlin / Dystrophy-associated fer-1-like protein / Fer-1-like protein 1


Mass: 237577.094 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Strep tag is cleaved from the C-terminus / Source: (gene. exp.) Homo sapiens (human) / Gene: DYSF, FER1L1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O75923
Has protein modificationN

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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: Dysferlin monomer / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.237295 MDa / Experimental value: NO
Source (natural)Organism: unidentified (others)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: UltrAuFoil
VitrificationCryogen name: ETHANE

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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: 81000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
2EPUimage acquisition
10cryoSPARCinitial Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 2.96 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 271263 / Symmetry type: POINT

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