The head domain of plakophilin-1 binds to desmoplakin and enhances its recruitment to desmosomes. Implications for cutaneous disease.
The contribution of desmosomes to epidermal integrity is evident in the inherited blistering disorder associated with the absence of a functional gene for plakophilin-1. To define the function of plakophilin-1 in desmosome assembly, interactions among the desmosomal cadherins, desmoplakin, and the armadillo family members plakoglobin and plakophilin-1 were examined. In transient expression assays, plakophilin-1 formed complexes with a desmoplakin amino-terminal domain and enhanced its recruitment to cell-cell borders; this recruitment was not dependent on the equimolar expression of desmosomal cadherins. In contrast to desmoplakin-plakoglobin interactions, the interaction between desmoplakin and plakophilin-1 was not mediated by the armadillo repeat domain of plakophilin-1 but by the non-armadillo head domain, as assessed by yeast two-hybrid and recruitment assays. We propose a model whereby plakoglobin serves as a linker between the cadherins and desmoplakin, whereas plakophilin-1 enhances lateral interactions between desmoplakin molecules. This model suggests that epidermal lesions in patients lacking plakophilin-1 are a consequence of the loss of integrity resulting from a decrease in binding sites for desmoplakin and intermediate filaments at desmosomes.
Kowalczyk
A P
AP
Department of Dermatology and the Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Hatzfeld
M
M
Bornslaeger
E A
EA
Kopp
D S
DS
Borgwardt
J E
JE
Corcoran
C M
CM
Settler
A
A
Green
K J
KJ
D000818:Animals; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D051180:Desmoplakins; D003896:Desmosomes / Q000378:metabolism*; D051191:Plakophilins; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism*; D011817:Rabbits; D012871:Skin Diseases / Q000503:physiopathology*; D051185:gamma Catenin
D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D051191:Plakophilins; D011506:Proteins; D051185:gamma Catenin