CELSR1, a core planar cell polarity protein, features a weakly adhesive and flexible cadherin ectodomain

Area of Science:

• Cell Biology
• Developmental Biology
• Structural Biology

Background:

• Planar cell polarity (PCP) is crucial for tissue development and relies on cell polarization and alignment.
• CELSR1, an atypical cadherin, is central to PCP, possessing a complex ectodomain with cadherin repeats and adhesion GPCR domains.
• Previous studies indicated CELSR1's homophilic adhesion, but the underlying mechanisms remained unclear.

Purpose of the Study:

• To investigate the adhesive properties and structural characteristics of CELSR1's extracellular cadherin (EC) repeats.
• To elucidate the mechanistic details of CELSR1-mediated cell adhesion.
• To identify the structural determinants governing CELSR1 function in planar cell polarity.

Main Methods:

• Bead aggregation assays were employed to assess the adhesive capabilities of CELSR1 EC repeats.
• Solution-based dimerization experiments were conducted for specific CELSR1 EC domains.
• Crystal structures of human CELSR1 EC1-4 and EC4-7 fragments were determined.
• Computational simulations were used to analyze the flexibility of EC4-7.

Main Results:

• Bead aggregation assays did not support strong adhesion mediated solely by CELSR1 EC repeats.
• CELSR1 EC1-4 demonstrated dimerization only at high concentrations in solution.
• Crystal structures revealed canonical folds for EC1-4 and EC4-7, with a non-canonical linker between EC5 and EC6.
• Experiments and simulations indicated flexibility at the EC5-6 linker, and EC7-MAD10 mediated dimerization.

Conclusions:

• CELSR1 cadherin repeats exhibit weak homophilic adhesion.
• The structural flexibility, particularly at the EC5-6 linker, and the EC7-MAD10 domain contribute to CELSR1-mediated dimerization and function.
• These findings provide mechanistic insights into the structural basis of CELSR1's role in planar cell polarity.