Structure of the human BBSome core complex.

Area of Science:

• Structural biology
• Molecular mechanisms of disease
• Cell biology

Background:

• The BBSome is a protein complex essential for primary cilia function and homeostasis.
• Malfunction of the BBSome leads to Bardet-Biedl syndrome (BBS), a severe ciliopathy.
• The BBSome acts as a cargo adapter, linking signaling proteins to the intraflagellar transport system, but its mechanism is unclear.

Purpose of the Study:

• To determine the high-resolution cryo-electron microscopy (cryo-EM) structure of a human BBSome core subcomplex.
• To elucidate the atomic-level architecture of the BBSome.
• To understand subunit interactions and the impact of disease-associated mutations.

Main Methods:

• High-resolution cryo-electron microscopy (cryo-EM)
• Structural analysis of a human heterohexameric BBSome core subcomplex

Main Results:

• The study presents the atomic-level structure of a human BBSome core subcomplex.
• The structure reveals detailed subunit interactions and how disease mutations disrupt them.
• The BBSome adopts an open conformation for binding to GTPase Arl6, with charged patches facilitating membrane and cargo interactions.

Conclusions:

• The determined structure provides a mechanistic basis for BBSome function in cargo recognition and transport.
• Understanding the structural basis of BBSome assembly and function is critical for deciphering Bardet-Biedl syndrome pathogenesis.
• This work lays the foundation for future therapeutic strategies targeting BBS-related ciliopathies.