title: The desmoglein-specific cytoplasmic region is intrinsically disordered in solution and interacts with multiple desmosomal protein partners.
abstract: The desmoglein-specific cytoplasmic region (DSCR) is a conserved region of unknown structure and function that uniquely defines the desmoglein family of cell adhesion molecules. It is the site of caspase cleavage during apoptosis, and its mutation is linked to cardiomyopathy. Here, we reveal that a 276-residue DSCR construct of human desmoglein 1 is intrinsically disordered and forms an interaction hub for desmosomal proteins. In solution, it contains 6.5% helical and 10.3% beta-strand structure based on circular dichroism spectroscopy. A single monomeric state with a predominantly unfolded structure is found by size-exclusion chromatography and analytical ultracentrifugation. Thermal stability assays and nuclear magnetic resonance spectroscopy reveal a nonglobular structure under a range of solution conditions. However, the introduction of detergent micelles increases structure to 18% helical and 16% beta-strand character, suggesting an inducible structure. The DSCR exhibits weak but specific interactions with plakoglobin, the plakin domain of desmoplakin, plakophilin 1, and the cytoplasmic domain of desmocollin 1. The desmoglein 1 membrane proximal region also interacts with all four DSCR ligands, strongly with plakoglobin and plakophilin and more weakly with desmoplakin and desmocollin 1. Thus, the DSCR is an intrinsically disordered functional domain with an inducible structure that, along with the membrane proximal region, forms a flexible scaffold for cytoplasmic assembly at the desmosome.
authors.affiliation: University of Birmingham, UK.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kami
authors.forename: Martyn
authors.initials: M
authors.lastname: Chidgey
authors.forename: Timothy
authors.initials: T
authors.lastname: Dafforn
authors.forename: Michael
authors.initials: M
authors.lastname: Overduin
mesh_terms: D000595:Amino Acid Sequence; D002942:Circular Dichroism; D051187:Desmocollins / Q000378:metabolism*; D051183:Desmoglein 1 / Q000737:chemistry* / Q000378:metabolism*; D051180:Desmoplakins / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D051191:Plakophilins / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D051185:gamma Catenin
chemical_list: C081560:DSC1 protein, human; C495297:DSG1 protein, human; D051187:Desmocollins; D051183:Desmoglein 1; D051180:Desmoplakins; C495292:JUP protein, human; C495335:PKP1 protein, human; D051191:Plakophilins; D051185:gamma Catenin