title: A variable cytoplasmic domain segment is necessary for γ-protocadherin trafficking and tubulation in the endosome/lysosome pathway.
abstract: Clustered protocadherins (Pcdhs) are arranged in gene clusters (α, β, and γ) with variable and constant exons. Variable exons encode cadherin and transmembrane domains and ~90 cytoplasmic residues. The 14 Pcdh-αs and 22 Pcdh-γs are spliced to constant exons, which, for Pcdh-γs, encode ~120 residues of an identical cytoplasmic moiety. Pcdh-γs participate in cell-cell interactions but are prominently intracellular in vivo, and mice with disrupted Pcdh-γ genes exhibit increased neuronal cell death, suggesting nonconventional roles. Most attention in terms of Pcdh-γ intracellular interactions has focused on the constant domain. We show that the variable cytoplasmic domain (VCD) is required for trafficking and organelle tubulation in the endolysosome system. Deletion of the constant cytoplasmic domain preserved the late endosomal/lysosomal trafficking and organelle tubulation observed for the intact molecule, whereas deletion or excision of the VCD or replacement of the Pcdh-γA3 cytoplasmic domain with that from Pcdh-α1 or N-cadherin dramatically altered trafficking. Truncations or internal deletions within the VCD defined a 26-amino acid segment required for trafficking and tubulation in the endolysosomal pathway. This active VCD segment contains residues that are conserved in Pcdh-γA and Pcdh-γB subfamilies. Thus the VCDs of Pcdh-γs mediate interactions critical for Pcdh-γ trafficking.
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: O'Leary
authors.forename: James E
authors.initials: JE
authors.lastname: Reilly
authors.forename: Hugo H
authors.initials: HH
authors.lastname: Hanson
authors.forename: Semie
authors.initials: S
authors.lastname: Kang
authors.forename: Nicole
authors.initials: N
authors.lastname: Lou
authors.forename: Greg R
authors.initials: GR
authors.lastname: Phillips
mesh_terms: D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D005810:Multigene Family; D009420:Nervous System / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: D000070585:Cadherin Related Proteins; D015820:Cadherins; C464785:Gamma-protocadherins