Disease relevance of ASULAM

• One member of this group is bullous pemphigoid antigen 1 (Bpag1)/dystonin, which has neuronal and muscle isoforms that consist of actin-binding and microtubule-binding domains at either end separated by a plakin domain and several spectrin repeats [1].
• The members of the plakin family of proteins recognized by paraneoplastic pemphigus antibodies include periplakin [2].
• The plakin family of linker proteins have been in the spotlight recently as critical components for embryo survival and, when mutated, the cause of diseases such as muscular dystrophy and cardiomyopathies [3].
• BACKGROUND: In select cases, lichen planus has been observed to be a paraneoplastic condition sometimes associated with paraneoplastic pemphigus, a disease featuring autoantibodies directed against plakin proteins, desmogleins 3 and 1, and a still uncharacterized 170-kd antigen [4].
• CONCLUSIONS: The presence and localization in tumours of B-lymphocyte clones against proteins of the plakin family and desmoglein 3 in skin may not be confined to PNP with Castleman disease, but is possibly a common mechanism in PNP associated with various tumours [5].

High impact information on ASULAM

• We have now isolated a third member of the nesprin family that lacks an ABD and instead binds to the plakin family member plectin, which can associate with the intermediate filament (IF) system [6].
• We find that the plakin repeats are inserted between the actin-binding domain and spectrin repeats, generating isoforms as large as 8,846 residues, which could span 400 nm [7].
• Our analysis of vab-10 reveals novel insights into the role of this plakin subfamily. vab-10 generates isoforms related either to plectin (termed VAB-10A) or to microtubule actin cross-linking factor plakins (termed VAB-10B) [8].
• Bullous pemphigoid antigen 1 (BPAG1) is a member of the plakin family with cytoskeletal linker properties [9].
• BPAG1-b is highly expressed in muscles, and has extra exons encoding a second IFBD between the plakin and SR-containing rod domains of BPAG1-a [9].

Biological context of ASULAM

• Kakapo is a large intracellular protein and contains structural domains also found in cytoskeletal-related vertebrate proteins (including plakin, dystrophin, and Gas2 family members). kakapo mutant embryos exhibit abnormal muscle-dependent tendon cell differentiation [10].
• The exon-intron structure of the mouse envoplakin gene is common to all members of the plakin family: the N-terminal protein domain is encoded by 21 small exons, and the central rod domain and the C-terminal globular domain are coded by a single large exon [11].
• Additional binding sites for the plakin domain of plectin on beta4 were identified in biochemical and yeast two-hybrid assays [12].
• Based on this structure and analysis of sequence conservation, we propose that the architecture of plakin domains is defined by two pairs of spectrin repeats interrupted by a putative Src-Homology 3 (SH3) domain [13].
• To further characterize this PNP antibody response, we produced fusion proteins of the homologous tail region of five plakin family members, including the recently cloned periplakin [2].

Anatomical context of ASULAM

• An epidermal plakin that integrates actin and microtubule networks at cellular junctions [14].
• Periplakin, a novel component of cornified envelopes and desmosomes that belongs to the plakin family and forms complexes with envoplakin [15].
• Here, we report on ACF7, a mammalian orthologue of the Drosophila kakapo plakin genetically involved in epidermal-muscle adhesion and neuromuscular junctions [14].
• The members of the plakin family of proteins serve as epidermal cytolinkers and components of cell-cell and cell-matrix adhesion complexes, i.e., desmosomes and hemidesmosomes, respectively [16].
• Envoplakin, a member of the plakin family of cytoskeletal linker proteins, is localized in desmosomes of stratified epithelial cells and is a component of the epidermal cornified envelope [17].

Gene context of ASULAM

• The plakin Short Stop and the RhoA GTPase are required for E-cadherin-dependent apical surface remodeling during tracheal tube fusion [18].
• Several proteins belonging to the plakin family of cytoskeletal linker proteins have recently been identified, including dystonin/Bpag1 and plectin [19].
• Dynamics and unexpected localization of the plakin binding protein, kazrin, in mouse eggs and early embryos [3].
• We have previously reported the cloning and partial characterization of Acf7, a novel member of the plakin family [19].
• The short C-terminal domain of periplakin is composed only of the linker domain, a region highly homologous between the plakin proteins [20].

Analytical, diagnostic and therapeutic context of ASULAM

• Immunoblotting of equal amounts of each plakin tail-glutathione S-transferase fusion protein with PNP sera revealed a strong reaction with the envoplakin tail domain [2].
• Interestingly, indirect immunofluorescence on rat bladder was negative and immunoblot analysis of the patient's serum on epidermal extracts demonstrated antiepidermal antibodies that only recognized the pemphigus vulgaris antigen desmoglein 3, with no antibodies directed against the different proteins of the plakin family [21].

References