Structural basis of human VANGL-PRICKLE interaction

Area of Science:

• Cell Biology
• Developmental Biology
• Structural Biology

Background:

• Planar cell polarity (PCP) governs cell and tissue organization during development.
• The VANGL-PRICKLE (PK) protein complex is a key regulator of PCP, but its structural details and functions remain largely unknown.
• Understanding the molecular mechanisms of PCP is vital for developmental biology and disease research.

Purpose of the Study:

• To elucidate the structural basis of the interaction between VANGL proteins and PRICKLE proteins.
• To investigate the functional role of PRICKLE1 in the localization of VANGL proteins within the cell.
• To provide molecular insights into the regulation of planar cell polarity.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine high-resolution structures of human VANGL1, VANGL2, and their complexes with PRICKLE1.
• Biochemical assays were employed to analyze the VANGL-PK interaction.
• Cell imaging experiments were conducted to visualize protein localization and function.

Main Results:

• Five cryo-EM structures of human VANGL1, VANGL2, and VANGL-PRICKLE1 complexes were resolved at 2.2-3.0 Å resolution.
• The molecular details of the VANGL-PK interaction were deciphered.
• PRICKLE1 was shown to target VANGL-containing intracellular vesicles to the peripheral cell membrane.

Conclusions:

• The study provides the first high-resolution structural insights into the VANGL-PK interaction, a critical component of the PCP pathway.
• PRICKLE1 plays a direct role in trafficking VANGL proteins to the cell periphery, influencing PCP establishment.
• These findings offer a foundation for further research into the molecular mechanisms of PCP and related developmental processes.