title: The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy-linked mutations.
abstract: Desmoplakin is a cytoplasmic desmosomal protein that plays a vital role in normal intercellular adhesion. Mutations in desmoplakin can result in devastating skin blistering diseases and arrhythmogenic right ventricular cardiomyopathy, a heart muscle disorder associated with ventricular arrhythmias, heart failure, and sudden death. The desmoplakin N-terminal region is a 1056-amino-acid sequence of unknown structure. It mediates interactions with other desmosomal proteins, is found in a variety of plakin proteins, and spans what has been termed the "plakin domain," which includes residues 180-1022 and consists of six spectrin repeats (SRs) and an Src homology 3 domain. Herein we elucidate the architecture of desmoplakin's plakin domain, as well as its constituent tandem SRs. Small-angle X-ray scattering analysis shows that the entire plakin domain has an "L" shape, with a long arm and a short arm held at a perpendicular angle. The long arm is 24.0 nm long and accommodates four stably folded SRs arranged in tandem. In contrast, the short arm is 17.9 nm in length and accommodates two independently folded repeats and an extended C-terminus. We show that mutations linked to arrhythmogenic right ventricular cardiomyopathy (K470E and R808C) cause local conformational alterations, while the overall folded structure is maintained. This provides the first structural and mechanistic insights into an entire plakin domain and provides a basis for understanding the critical role of desmoplakin in desmosome function.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Caezar
authors.initials: C
authors.lastname: Al-Jassar
authors.forename: Timothy
authors.initials: T
authors.lastname: Knowles
authors.forename: Mark
authors.initials: M
authors.lastname: Jeeves
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kami
authors.forename: Elijah
authors.initials: E
authors.lastname: Behr
authors.forename: Hennie
authors.initials: H
authors.lastname: Bikker
authors.forename: Michael
authors.initials: M
authors.lastname: Overduin
authors.forename: Martyn
authors.initials: M
authors.lastname: Chidgey
mesh_terms: D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D051180:Desmoplakins / Q000737:chemistry* / Q000235:genetics; D003896:Desmosomes / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D020449:Repetitive Sequences, Amino Acid; D013049:Spectrin / Q000737:chemistry; D018909:src Homology Domains
chemical_list: C495294:DSP protein, human; D051180:Desmoplakins; D013049:Spectrin