title: Single-cell identity generated by combinatorial homophilic interactions between α, β, and γ protocadherins.
abstract: Individual mammalian neurons stochastically express distinct repertoires of α, β, and γ protocadherin (Pcdh) proteins, which function in neural circuit assembly. We report that all three subfamilies of clustered Pcdhs can engage in specific homophilic interactions, that cell surface delivery of Pcdhα isoforms requires cis interactions with other Pcdhs, and that the extracellular cadherin domain EC6 plays a critical role in this process. Examination of homophilic interactions between specific combinations of multiple Pcdh isoforms revealed that Pcdh combinatorial recognition specificities depend on the identity of all of the expressed isoforms. A single mismatched Pcdh isoform can interfere with these combinatorial homophilic interactions. A theoretical analysis reveals that assembly of Pcdh isoforms into multimeric recognition units and the observed tolerance for mismatched isoforms can generate cell surface diversity sufficient for single-cell identity. However, the competing demands of nonself discrimination and self-recognition place limitations on the mechanisms by which homophilic recognition units can function.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, 701 W 168th Street, New York, NY 10032, USA.
authors.forename: Chan Aye
authors.initials: CA
authors.lastname: Thu
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, 701 W 168th Street, New York, NY 10032, USA.
authors.forename: Weisheng V
authors.initials: WV
authors.lastname: Chen
authors.affiliation: Center for Computational Biology and Bioinformatics, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of System Biology, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Howard Hughes Medical Institute.
authors.forename: Rotem
authors.initials: R
authors.lastname: Rubinstein
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, 701 W 168th Street, New York, NY 10032, USA.
authors.forename: Maxime
authors.initials: M
authors.lastname: Chevee
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, 1150 St. Nicholas Avenue, Russ Berrie Pavilion, New York, NY 10032, USA.
authors.forename: Holly N
authors.initials: HN
authors.lastname: Wolcott
authors.affiliation: Center for Computational Biology and Bioinformatics, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of System Biology, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Howard Hughes Medical Institute.
authors.forename: Klara O
authors.initials: KO
authors.lastname: Felsovalyi
authors.affiliation: Department of Neuroscience, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Tapia
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, 1150 St. Nicholas Avenue, Russ Berrie Pavilion, New York, NY 10032, USA; Department of System Biology, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, 1150 St. Nicholas Avenue, Russ Berrie Pavilion, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of System Biology, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Howard Hughes Medical Institute. Electronic address: bh6@columbia.edu.
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, 701 W 168th Street, New York, NY 10032, USA. Electronic address: tm2472@cumc.columbia.edu.
authors.forename: Tom
authors.initials: T
authors.lastname: Maniatis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry* / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D000070585:Cadherin Related Proteins; D015820:Cadherins; C464785:Gamma-protocadherins; D020033:Protein Isoforms