title: Coiled coils ensure the physiological ectodomain shedding of collagen XVII.
abstract: α-Helical coiled coils, frequent protein oligomerization motifs, are commonly observed in vital proteins. Here, using collagen XVII as an example, we provide evidence for a novel function of coiled coils in the regulation of ectodomain shedding. Transmembrane collagen XVII, an epithelial cell surface receptor, mediates dermal-epidermal adhesion in the skin, and its dysfunction is linked to human skin blistering diseases. The ectodomain of this collagen is constitutively shed from the cell surface by proteinases of a disintegrin and metalloprotease family; however, the mechanisms regulating shedding remain elusive. Here, we used site-specific mutagenesis to target the coiled-coil heptad repeats within the juxtamembranous, extracellular noncollagenous 16th A (NC16A) domain of collagen XVII. This resulted in a substantial increase of ectodomain shedding, which was not mediated by disintegrin and metalloproteases. Instead, conformational changes induced by the mutation(s) unmasked a furin recognition sequence that was used for cleavage. This study shows that apart from their functions in protein oligomerization, coiled coils can also act as regulators of ectodomain shedding depending on the biological context.
authors: Department of Dermatology, Freiburg University Medical Center, University of Freiburg, 79104 Freiburg, Germany. nishie@med.hokudai.ac.jp
authors: Wataru
authors: W
authors: Nishie
authors: Joanna
authors: J
authors: Jackow
authors: Silke C
authors: SC
authors: Hofmann
authors: Claus-Werner
authors: CW
authors: Franzke
authors: Leena
authors: L
authors: Bruckner-Tuderman
mesh_terms: D020816:Amino Acid Motifs; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001768:Blister / Q000235:genetics / Q000378:metabolism; D045683:Furin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D045726:Metalloproteases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D024041:Non-Fibrillar Collagens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D012867:Skin / Q000737:chemistry / Q000378:metabolism*; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D045683:Furin; D045726:Metalloproteases; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII; C468731:FURIN protein, human