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TitleStructural insights into lipid membrane binding by human ferlins.
Journal, issue, pagesEMBO J, Vol. 44, Issue 14, Page 3926-3958, Year 2025
Publish dateMay 28, 2025
AuthorsConstantin Cretu / Aleksandar Chernev / Csaba Zoltán Kibédi Szabó / Vladimir Pena / Henning Urlaub / Tobias Moser / Julia Preobraschenski /
PubMed AbstractFerlins 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.
External linksEMBO J / PubMed:40437073 / PubMed Central
MethodsEM (single particle)
Resolution2.56 - 3.54 Å
Structure data

51902

9h6x

EMDB-51902, PDB-9h6x:
Cryo-EM structure of lipid-bound human myoferlin (25 mol% DOPS/5 mol% PI(4,5)P2 nanodisc)
Method: EM (single particle) / Resolution: 2.56 Å

53222

9qkv

EMDB-53222, PDB-9qkv:
Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc (15 mol% DOPS, 5 mol% Cholesterol)
Method: EM (single particle) / Resolution: 2.74 Å

53225

9qle

EMDB-53225, PDB-9qle:
Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc (15 mol% DOPS, 2 mol% PI(4,5)P2)
Method: EM (single particle) / Resolution: 2.8 Å

53226

9qlf

EMDB-53226, PDB-9qlf:
Human myoferlin (1-1997) in complex with an MSP2N2 lipid nanodisc (25 mol% DOPS, 5 mol% PI(4,5)P2 and 5 mol% Cholesterol)
Method: EM (single particle) / Resolution: 2.65 Å

53229

9qln

EMDB-53229, PDB-9qln:
Human myoferlin (1-1997) in the lipid-free, Ca2+-bound state
Method: EM (single particle) / Resolution: 3.2 Å

53233

9qls

EMDB-53233, PDB-9qls:
Human dysferlin (1-2017) in the lipid-free, Ca2+-bound state
Method: EM (single particle) / Resolution: 3.54 Å

Chemicals

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

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Ferlin / multi-C2 domain protein / tail-anchored membrane protein / vesicle docking and fusion / membrane remodeling / Ferlins / myoferlin / multi-C2 domains / lipid nanodisc / multi-C2 domain / dysferlin

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