The Head Domain of Plakophilin-1 Binds to Desmoplakin and Enhances Its Recruitment to Desmosomes
IMPLICATIONS FOR CUTANEOUS DISEASE*
- Andrew P. Kowalczyk‡§,
- Mechthild Hatzfeld¶,
- Elayne A. Bornslaeger‖,
- Daniel S. Kopp‖,
- Jeffrey E. Borgwardt‖,
- Connie M. Corcoran‖,
- Aaron Settler‖ and
- Kathleen J. Green‡‖**
- From the Departments of ‖Pathology and‡Dermatology and the Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611 and the¶Molecular Biology Group of the Medical Faculty, Martin-Luther-University of Halle, Magdeburger Strasse 18, 06097 Halle/Saale, Germany
Abstract
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.
Footnotes
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↵* This work was supported by March of Dimes Grant FY98–0073, and by National Institutes of Health Grants RO1AR43380 and PO1DE12328 (to K. J. G.) and K01 AR02039 (to A. P. K.), and by DFG Grants Ha 1791/3-1, 3-2, and 3-3 (to M. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ Present address: Dept. of Dermatology, Emory University School of Medicine, Woodruff Memorial Bldg., Rm. 5007, 1639 Pierce Dr., Atlanta, GA 30322.
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↵** To whom correspondence should be addressed: Dept. of Pathology, Northwestern University Medical School, 303 East Chicago Ave., Chicago, IL 60611. Tel.: 312-503-5300; Fax: 312-503-8240; E-mail:kgreen{at}nwu.edu.
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↵2 M. Hatzfeld, manuscript in preparation.
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↵3 M. Hatzfeld, M. Ruediger, and E. Klaile, unpublished observations.
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↵4 M. Hatzfeld, unpublished observations.
- Abbreviations:
- PKP-1
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plakophilin-1
- Ab
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antibody
- mAb
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monoclonal antibody
- CMV
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cytomegalovirus
- PCR
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polymerase chain reaction
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- Received March 8, 1999.
- Revision received April 16, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
