Protocadherin cis-dimer architecture and recognition unit diversity.

Area of Science:

• Neuroscience
• Molecular Biology
• Structural Biology

Background:

• Clustered protocadherins (Pcdhs) are crucial for neural patterning, mediating self-recognition and non-self-discrimination in vertebrate neurons.
• Neurons express a stochastic subset of Pcdh isoforms, forming diverse cis-dimers that dictate cellular interactions.

Purpose of the Study:

• To elucidate the structural basis of Pcdh cis-dimerization.
• To understand how Pcdh structure influences self-recognition and cell surface transport.

Main Methods:

• X-ray crystallography to determine the structure of a PcdhγB7 cis-homodimer.
• Site-directed mutagenesis to investigate the functional role of the dimerization interface.
• Sequence analysis to infer dimerization mechanisms across Pcdh isoforms.

Main Results:

• The structure of a PcdhγB7 cis-homodimer reveals an asymmetric interface involving EC5 and EC6 domains.
• Mutations at this interface disrupt Pcdh cis-dimerization and cell surface transport.
• The asymmetric interface potentially doubles the Pcdh recognition repertoire.

Conclusions:

• The Pcdh dimerization interface structure explains isoform-specific interaction restrictions, such as the inability of alpha-Pcdhs to form homodimers.
• The findings provide a structural framework for understanding how Pcdh diversity contributes to precise neural wiring and self-avoidance mechanisms.