Uncovering the BIN1-SH3 interactome underpinning centronuclear myopathy

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• The Bridging Integrator 1 (BIN1) protein's SH3 domain is crucial for membrane remodeling and its truncation causes centronuclear myopathy.
• BIN1 interacts with dynamin 2 (DNM2), and variants in this interaction are linked to neuromuscular disorders.

Purpose of the Study:

• To investigate the impact of uncharacterized BIN1 SH3 domain variants on BIN1-DNM2 interactions.
• To identify novel BIN1 interaction partners and elucidate the pathomechanism of BIN1-related centronuclear myopathy.
• To explore the role of BIN1 in mitosis and cell division.

Main Methods:

• In vitro and cell-based assays to assess BIN1-DNM2 interactions.
• Affinity interactomics to identify BIN1 binding partners proteome-wide.
• Analysis of proteome-wide affinity perturbation caused by BIN1 mutations.

Main Results:

• Several naturally occurring BIN1 SH3 domain variants were identified as potentially harmful, linking them to neuromuscular disorders.
• Hundreds of new BIN1 interaction partners were discovered, many involved in cell division.
• BIN1 mutations were shown to cause significant proteome-wide affinity perturbations.

Conclusions:

• BIN1 SH3 domain variants can lead to centronuclear myopathy through disrupted interactions.
• BIN1 plays a significant role in mitosis, and its novel interactors offer new insights into pathomechanisms.
• Unbiased affinity interactomics is essential for understanding the complex role of BIN1 in cellular processes and disease.