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From Proteopedia

Revision as of 09:51, 29 November 2025

Structure

This page describes the cryo-EM structure of the human planar cell polarity (PCP) core protein **Vangl1**, determined at high resolution and deposited as **PDB ID: 8ZXD**. The structure reveals the oligomeric assembly and membrane-embedded architecture of Vangl1.

Function

Vangl1 is a core component of the **planar cell polarity pathway**, required for the asymmetric organization of epithelial cells. It interacts with other PCP proteins such as Prickle, Disheveled, and Celsa, helping establish directional cues during development.

Disease relevance

Mutations in Vangl1 are associated with **neural tube defects**, disrupted epithelial morphogenesis, and defects in directional cell movement. Understanding the structure of Vangl1 (8ZXD) provides insights into how disease-causing mutations impair PCP signaling.

Structural highlights

• The 8ZXD cryo-EM structure reveals Vangl1 forms a **stable oligomeric assembly**. • Multiple **transmembrane helices** form a curved architecture suited for membrane integration. • The **cytoplasmic C-terminal tail** contains potential interaction motifs for PCP partners. • Structural comparisons indicate how mutations may disrupt folding, oligomerization, or partner binding.

Structure and Functional Insights of human VANGL1

Summary

VANGL1 is a core component of the planar cell polarity (PCP) pathway, which coordinates the orientation of cells across the epithelial plane. This is critical for tissue morphogenesis and developmental processes. Mutations in VANGL1 are linked to congenital defects, including neural tube malformations.

A recent cryo‑electron microscopy (cryo‑EM) study resolved the full-length human VANGL1 structure at 2.9 Å resolution (PDB: 8ZXD), revealing that VANGL1 assembles as a **hexamer**, organized as a **dimer of trimers**. Each trimer consists of four transmembrane helices per protomer followed by cytosolic “hand” and “stick” domains.

The central feature of the hexamer is a **large vestibule**, potentially solvent-filled and sealed from the cytosol when two trimers dimerize. The physiological role of this vestibule is still under investigation. Functional assays suggest that oligomerization enhances VANGL1 binding to the cytosolic effector Prickle1 (Pk1).

Mapping of disease-associated mutations onto the 3D structure indicates that many mutations cluster around the transmembrane region or central vestibule. This implies that disrupted lipid binding, oligomerization, or vestibule integrity may underlie developmental defects.

Overall, the structural data provides a framework for understanding how VANGL1 oligomerization, membrane insertion, and effector interactions contribute to PCP signaling and how mutations cause disease.

Key structural insights

• 8ZXD shows a hexameric assembly (dimer of trimers).
• TM helices form the trimerization core.
• Cytosolic 'stick' domain mediates dimer–dimer contacts.
• Central vestibule appears lipid-binding but not a channel.

Images

Image:Vangl1 trimer vestibule.png Image:Vangl1 stick interface.png

3D Scenes (interactive)

Overall hexamer: Scene:Vangl1_overview Trimer + vestibule: Scene:Vangl1_trimer_vestibule Stick-domain interface: Scene:Vangl1_stick_interface Mutations highlighted: Scene:Vangl1_mutations

Methods / Data sources

PDB: 8ZXD. Cryo-EM map: EMD-60540.

References

^[1]

PyMOL Scripts

1. Overall hexamer view

fetch 8ZXD, async=0 show cartoon color cyan, chain A color yellow, chain B color salmon, chain C color gray, chain D color green, chain E color orange, chain F orient png VANGL1_overview.png, dpi=300

1. Membrane/side view

fetch 8ZXD, async=0 show cartoon show surface, chain A+B+C+D+E+F set opaque_background, off orient png VANGL1_membrane_view.png, dpi=300

1. Central vestibule cross-section

fetch 8ZXD, async=0 show cartoon slice z, 0.0 # adjust plane to intersect vestibule png VANGL1_central_vestibule.png, dpi=300