Protocadherin <i>cis</i>-dimer architecture and recognition unit diversity.

Abstract

Clustered protocadherins (Pcdhs) mediate numerous neural patterning functions, including neuronal self-recognition and non-self-discrimination to direct self-avoidance among vertebrate neurons. Individual neurons stochastically express a subset of Pcdh isoforms, which assemble to form a stochastic repertoire of <i>cis</i>-dimers. We describe the structure of a PcdhγB7 <i>cis</i>-homodimer, which includes the membrane-proximal extracellular cadherin domains EC5 and EC6. The structure is asymmetric with one molecule contributing interface surface from both EC5 and EC6, and the other only from EC6. Structural and sequence analyses suggest that all Pcdh isoforms will dimerize through this interface. Site-directed mutants at this interface interfere with both Pcdh <i>cis</i>-dimerization and cell surface transport. The structure explains the known restrictions of <i>cis</i>-interactions of some Pcdh isoforms, including α-Pcdhs, which cannot form homodimers. The asymmetry of the interface approximately doubles the size of the recognition repertoire, and restrictions on <i>cis</i>-interactions among Pcdh isoforms define the limits of the Pcdh recognition unit repertoire.