Protocadherin cis-dimer architecture and recognition unit diversity

Kerry M. Goodman, Rotem Rubinstein, Hanbin Dan, Fabiana Bahna, Seetha Mannepalli, Göran Ahlsén, Chan Aye Thu, Rosemary V. Sampogna, Tom Maniatis, Barry Honig, Lawrence Shapiro

Research output: Contribution to journalArticlepeer-review

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 cis-dimers. We describe the structure of a PcdhγB7 cis-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 cis-dimerization and cell surface transport. The structure explains the known restrictions of cis-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 cis-interactions among Pcdh isoforms define the limits of the Pcdh recognition unit repertoire.

Original languageEnglish
Pages (from-to)E9829-E9837
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number46
DOIs
StatePublished - 14 Nov 2017
Externally publishedYes

Keywords

  • Clustered protocadherin
  • Crystal structure
  • Neuronal self-avoidance
  • Protein–protein interaction
  • Self-recognition

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