Structural insights into lipid membrane binding by human ferlins

Area of Science:

• Membrane biology
• Protein structure and function
• Molecular medicine

Background:

• Ferlins are essential multi-C2 domain proteins involved in Ca²⁺-dependent vesicle fusion.
• Despite their disease relevance, the mechanism of ferlin-lipid membrane interaction remains unclear.

Purpose of the Study:

• To elucidate the near-complete structures of human myoferlin and dysferlin in Ca²⁺- and lipid-bound states.
• To understand the mechanistic basis of ferlin-mediated membrane remodeling and fusion.

Main Methods:

• Near-complete cryo-electron microscopy (cryo-EM) structure determination of human myoferlin and dysferlin.
• Biophysical probing of ferlin domain interfaces.

Main Results:

• Ferlins form compact, ring-like structures upon binding to lipid membranes.
• The C2C-C2D region forms a rigid arch, while C2B, C2F, and C2G domains undergo Ca²⁺-dependent conformational changes to close the ring.
• This Ca²⁺-triggered ring closure facilitates tight interaction with the target membrane.

Conclusions:

• The study reveals the general structural principles of human ferlins, characterized by a dynamic ring-like architecture.
• This provides a mechanistic framework for ferlin-lipid interactions and Ca²⁺-dependent membrane fusion.
• The findings offer insights into ferlin-related cellular functions and human disease mechanisms.