5dzz | pdb_00005dzz
Structural characterization of intermediate filaments binding domain of desmoplakin
Structural highlights
DiseaseDESP_HUMAN Defects in DSP are the cause of palmoplantar keratoderma striate type 2 (SPPK2) [MIM:612908; also known as keratosis palmoplantaris striata II. SPPK2 is characterized by skin thickening in the palms (linear pattern) and the soles (island-like pattern) and flexor aspect of the fingers. Abnormalities of the nails, the teeth and the hair are rarely present.[1] Defects in DSP are the cause of cardiomyopathy dilated with woolly hair and keratoderma (DCWHK) [MIM:605676; also known as Carvajal syndrome or palmoplantar keratoderma with left ventricular cardiomyopathy and woolly hair. DCWHK is an autosomal recessive cardiocutaneous syndrome characterized by a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair, and dilated left ventricular cardiomyopathy.[2] Defects in DSP are the cause of familial arrhythmogenic right ventricular dysplasia type 8 (ARVD8) [MIM:607450; also known as arrhythmogenic right ventricular cardiomyopathy 8 (ARVC8). ARVD is an autosomal dominant disease characterized by partial degeneration of the myocardium of the right ventricle, electrical instability, and sudden death. It is clinically defined by electrocardiographic and angiographic criteria; pathologic findings, replacement of ventricular myocardium with fatty and fibrous elements, preferentially involve the right ventricular free wall.[3] [4] [5] Defects in DSP are the cause of skin fragility-woolly hair syndrome (SFWHS) [MIM:607655. SFWHS is an autosomal recessive genodermatosis characterized by focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs, and woolly hair with varying degrees of alopecia.[6] Defects in DSP are the cause of epidermolysis bullosa lethal acantholytic (EBLA) [MIM:609638. EBLA is characterized by severe fragility of skin and mucous membranes. The phenotype is lethal in the neonatal period because of immense transcutaneous fluid loss. Typical features include universal alopecia, neonatal teeth, and nail loss. Histopathology of the skin shows suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. FunctionDESP_HUMAN Major high molecular weight protein of desmosomes. Involved in the organization of the desmosomal cadherin-plakoglobin complexes into discrete plasma membrane domains and in the anchoring of intermediate filaments to the desmosomes. Publication Abstract from PubMedDesmoplakin (DP) is a cytoskeletal linker protein that connects the desmosomal cadherin/plakoglobin/plakophilin complex to intermediate filaments (IFs). The C-terminal region of DP (DPCT) mediates IF binding, and contains three plakin repeat domains (PRDs), termed PRD-A, PRD-B and PRD-C. Previous crystal structures of PRDs B and C revealed that each is formed by 4.5 copies of a plakin repeat (PR) and has a conserved positively charged groove on its surface. Although PRDs A and B are linked by just four amino acids, B and C are separated by a 154 residue flexible linker, which has hindered crystallographic analysis of the full DPCT. Here we present the crystal structure of a DPCT fragment spanning PRDs A and B, and elucidate the overall architecture of DPCT by small angle X-ray scattering (SAXS) analysis. The structure of PRD-A is similar to that of PRD-B, and the two domains are arranged in a quasi-linear arrangement, and separated by a 4 amino acid linker. Analysis of the B-C linker region using secondary structure prediction and the crystal structure of a homologous linker from the cytolinker periplakin suggests that the N-terminal ~100 amino acids of the linker form two PR-like motifs. SAXS analysis of DPCT indicates an elongated but non-linear shape with Rg = 51.5 A and Dmax = 178 A. These data provide the first structural insights into an IF binding protein containing multiple PRDs and provide a foundation for studying the molecular basis of DP-IF interactions. Structure of the Intermediate Filament-Binding Region of Desmoplakin.,Kang H, Weiss TM, Bang I, Weis WI, Choi HJ PLoS One. 2016 Jan 25;11(1):e0147641. doi: 10.1371/journal.pone.0147641., eCollection 2016. PMID:26808545[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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