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At least 19 recordsLinked to original sources
PubMed2006

Structural analysis of the plakin domain of bullous pemphigoid antigen1 (BPAG1) suggests that plakins are members of the spectrin superfamily.

Bullous pemphigoid antigen 1 (BPAG1) is a member of the plakin family of proteins. The plakins are multi-domain proteins that have been shown to interact with microtubules, actin filaments and intermediate filaments, as well as proteins found in cellular junctions. These interactions are mediated through different domains on the plakins. The interactions between plakins and components of specialized cell junctions such as desmosomes and hemidesmosomes are mediated through the so-called plakin domain, which is a common feature of the plakins. We report the crystal structure of a stable fragment from BPAG1, residues 226-448, defined by limited proteolysis of the whole plakin domain. The structure, determined by single-wavelength anomalous diffraction phasing from a selenomethionine-substituted crystal at 3.0 A resolution, reveals a tandem pair of triple helical bundles closely related to spectrin repeats. 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.

Amino Acid Sequence↗
PubMed1998

The members of the plakin family of proteins recognized by paraneoplastic pemphigus antibodies include periplakin.

Sera of patients with paraneoplastic pemphigus (PNP) characteristically immunoprecipitate five proteins, observations confirmed with the sera examined in this study. The proteins characterized thus far as autoantigens in PNP all belong to the plakin family of proteins and include desmoplakin, the 230 kDa bullous pemphigoid antigen, and envoplakin. The pattern of bands precipitated from metabolically labeled human keratinocyte extracts by each PNP serum was different, suggesting varying titers of antibodies against unique epitopes in various plakin family members. 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. 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. Each sera also recognized periplakin, and certain sera recognized desmoplakin and plectin, and, weakly, bullous pemphigoid antigen 1. PNP sera were affinity purified with periplakin and envoplakin tail fusion proteins. Immunoprecipitation and immunoblotting with these affinity purified antibodies revealed shared as well as unique epitopes in the tail domains of these plakins. This study indicates that a homologous region in the carboxy-terminus of plakins, including the newly characterized periplakin, serves as an antigenic site in PNP.

Amino Acid Sequence↗
PubMed2002

Plakins: a family of versatile cytolinker proteins.

By connecting cytoskeletal elements to each other and to junctional complexes, the plakin family of cytolinkers plays a crucial role in orchestrating cellular development and maintaining tissue integrity. Plakins are built from combinations of interacting domains that bind to microfilaments, microtubules, intermediate filaments, cell-adhesion molecules and members of the armadillo family. Plakins are involved in both inherited and autoimmune diseases that affect the skin, neuronal tissue, and cardiac and skeletal muscle. Here, we describe the members of the plakin family and their interaction partners, and give examples of the cellular defects that result from their dysfunction.

Amino Acid Sequence↗
PubMed1964

SEROLOGICAL RELATIONSHIPS AMONG BETA-LYSIN, PLAKIN, AND LEUKIN.

Donaldson, D. M. (Brigham Young University, Provo, Utah), R. S. Jensen, B. M. Jensen, and A. Matheson. Serological relationships among beta-lysin, plakin, and leukin. J. Bacteriol. 88:-1049 1055. 1964.-beta-Lysin is a substance which has been separated from normal serum and which is bactericidal for a variety of gram-positive bacteria including Bacillus subtilis. Purified beta-lysin is not denatured at 97 C for 15 min. The bactericidal activity of six of nine beta-lysin preparations was unaltered at 97 C for 30 min and was depressed 50% in the other three preparations. After 120 min at 97 C, the bactericidal activity was between 13 and 25% of normal. beta-Lysin was completely inactivated at 120 C for 15 min. Antisera prepared in guinea pigs against purified rabbit beta-lysin neutralized the bactericidal activities of purified beta-lysin, normal rabbit serum, platelet extracts, and purified plakin. This serological relationship between beta-lysin and plakin was also demonstrated by the observation that antisera against platelets neutralized the bactericidal activities of serum, platelet extracts, and purified beta-lysin. When anti-beta-lysin serum was tested against crude bactericidal extracts of leukocytes and purified leukin, no neutralization of these bactericidal substances was measurable. The results of this study are in accord with conclusions made in previous studies that platelets are a primary source of serum beta-lysin and that leukocytes contribute little, if any, to this type of serum bactericidal activity. Ouchterlony tests, in combination with the neutralization studies, indicated that the antigen-antibody system involved in the neutralization of beta-lysin may be a nonprecipitating system.

Animals↗
PubMed1997

The plakin family: versatile organizers of cytoskeletal architecture.

Desmoplakin, plectin, bullous pemphigoid antigen 1 and envoplakin are four sequence-related proteins--recently named the plakin family--that localize to intermediate filaments and filament attachment sites at the plasma membrane. New interest in the plakins has been stimulated by the discoveries that they can link different cytoskeletal elements together and that loss of plakin function can cause diseases of the skin and other tissues.

Alternative Splicing↗
PubMed2000

An epidermal plakin that integrates actin and microtubule networks at cellular junctions.

Plakins are cytoskeletal linker proteins initially thought to interact exclusively with intermediate filaments (IFs), but recently were found to associate additionally with actin and microtubule networks. Here, we report on ACF7, a mammalian orthologue of the Drosophila kakapo plakin genetically involved in epidermal-muscle adhesion and neuromuscular junctions. While ACF7/kakapo is divergent from other plakins in its IF-binding domain, it has at least one actin (K(d) = 0.35 microM) and one microtubule (K(d) approximately 6 microM) binding domain. Similar to its fly counterpart, ACF7 is expressed in the epidermis. In well spread epidermal keratinocytes, ACF7 discontinuously decorates the cytoskeleton at the cell periphery, including microtubules (MTs) and actin filaments (AFs) that are aligned in parallel converging at focal contacts. Upon calcium induction of intercellular adhesion, ACF7 and the cytoskeleton reorganize at cell-cell borders but with different kinetics from adherens junctions and desmosomes. Treatments with cytoskeletal depolymerizing drugs reveal that ACF7's cytoskeletal association is dependent upon the microtubule network, but ACF7 also appears to stabilize actin at sites where microtubules and microfilaments meet. We posit that ACF7 may function in microtubule dynamics to facilitate actin-microtubule interactions at the cell periphery and to couple the microtubule network to cellular junctions. These attributes provide a clear explanation for the kakapo mutant phenotype in flies.

Actin Cytoskeleton↗
PubMed2005

Microtubule actin crosslinking factor 1b: a novel plakin that localizes to the Golgi complex.

MACF1 (microtubule actin crosslinking factor), also called ACF7 (actin crosslinking family 7) is a cytoskeletal linker protein that can associate with both actin filaments and microtubules. We have identified a novel alternatively spliced isoform of MACF1. We named this isoform MACF1b and renamed the original isoform MACF1a. MACF1b is identical to MACF1a, except that it has a region containing plakin (or plectin) repeats in the middle of the molecule. MACF1b is ubiquitously expressed in adult tissues with especially high levels in the lung. We studied the subcellular localization of MACF1b proteins in mammalian cell lines. In two lung cell lines, MACF1b was chiefly localized to the Golgi complex. Upon treatments that disrupt the Golgi complex, MACF1b redistributed into the cytosol, but remained co-localized with the dispersed Golgi ministacks. MACF1b proteins can be detected in the enriched Golgi fraction by western blotting. The domain of MACF1b that targets it to the Golgi was found at the N-terminal part of the region that contains the plakin repeats. Reducing the level of MACF1 proteins by small-interfering RNA resulted in the dispersal of the Golgi complex.

Animals↗
PubMed2005

Dynamics and unexpected localization of the plakin binding protein, kazrin, in mouse eggs and early embryos.

The cell uses the cytoskeleton in virtually every aspect of cell survival and function. One primary function of the cytoskeleton is to connect to and stabilize intercellular junctions. To accomplish this task, microtubules, actin filaments, and intermediate filaments utilize cytolinker proteins, which physically bind the cytoskeletal filament to the core proteins of the adhesion junction. 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. Here, we reveal the dynamics of a recently discovered plakin binding protein, kazrin (kaz), during early mouse development. Kaz was originally found in adult tissues, primarily epidermis, linking periplakin to the plasma membrane and colocalizing with desmoplakin in desmosomes. Using reverse transcriptase-polymerase chain reaction, Western blots, and confocal microscopy, we found kaz in unfertilized eggs associated with the spindle apparatus and cytoskeletal sheets. As quickly as 5 min after egg activation, kaz relocates to a diffuse peri-spindle position, followed 20-30 min later by clear localization to the presumptive cytokinetic ring. Before the blastocyst stage of development, kaz associates with the nuclear matrix in a cell cycle-dependent manner, and also associates with the cytoplasmic actin cytoskeleton. After blastocyst formation, kaz localization and potential function(s) become highly complex as it is found associating with cell-cell junctions, the cytoskeleton, and nucleus. Postimplantation stages of development reveal that kaz retains a multifunctional, tissue-specific role as it is detected at diverse locations in various embryonic tissue types.

Animals↗
PubMed2001

Epiplakin, a novel member of the Plakin family originally identified as a 450-kDa human epidermal autoantigen. Structure and tissue localization.

A 450-kDa human epidermal autoantigen was originally identified as a protein that reacted with the serum from an individual with a subepidermal blistering disease. Molecular cloning of this protein has now shown that it contains 5065 amino acids and has a molecular mass of 552 kDa. As reported previously this protein, which we call epiplakin, belongs to the plakin family, but it has some very unusual features. Epiplakin has 13 domains that are homologous to the B domain in the COOH-terminal region of desmoplakin. The last five of these B domains, together with their associated linker regions, are particularly strongly conserved. However, epiplakin lacks a coiled-coil rod domain and an amino-terminal domain, both of which are found in all other known members of the plakin family. Furthermore, no dimerization motif was found in the sequence. Thus, it is likely that epiplakin exists in vivo as a single-chain structure. Epitope mapping experiments showed that the original patient's serum recognized a sequence unique to epiplakin, which was not found in plectin. Immunofluorescence staining revealed the presence of epiplakin in whole sheets of epidermis and esophagus, in glandular cells of eccrine sweat and parotid glands and in mucous epithelial cells in the stomach and colon.

Amino Acid Sequence↗
PubMed1999

Analysis of the desmoplakin gene reveals striking conservation with other members of the plakin family of cytolinkers.

Members of the plakin family of cytolinker proteins integrate filaments into cellular networks and anchor these networks to the plasma membrane. Their importance is supported by the existence of cell and tissue fragility disorders caused by mutations in certain family members. In this study, the human gene encoding desmoplakin (DSP) was characterized and its structure compared with the related family members: plectin, bullous pemphigoid antigen 1 (BPAG1), envoplakin (EVPL) and periplakin (PPL). Sequence analysis of genomic clones was carried out in combination with a PCR-based strategy to define intron-exon borders. DSP was mapped using the GB4 radiation hybrid mapping panel to the interval between markers D6S296 and AFM043 x f2, corresponding to cytogenetic band 6p24. In addition, the murine gene (Dsp) was mapped to mouse chromosome 13 by interspecific backcross mapping. DSP encompasses approximately 45 kb organized into 24 exons and 23 introns, and the pattern of intron-exon borders bears a striking resemblance to other members of the plakin family. Notable features include the fact that a single large exon encodes the entire C-terminus of each gene. In contrast, the N-termini comprise numerous smaller exons with conservation of many intron-exon borders. Detailed characterization and mapping of these genes will facilitate their further evaluation as targets of genetic disorders and provide insights into the evolutionary relationships among molecules in this emerging gene family.

Amino Acid Sequence↗
PubMed1997

Periplakin, a novel component of cornified envelopes and desmosomes that belongs to the plakin family and forms complexes with envoplakin.

The cornified envelope is a layer of transglutaminase cross-linked protein that is assembled under the plasma membrane of keratinocytes in the outermost layers of the epidermis. We have determined the cDNA sequence of one of the proteins that becomes incorporated into the cornified envelope of cultured epidermal keratinocytes, a protein with an apparent molecular mass of 195 kD that is encoded by a mRNA with an estimated size of 6.3 kb. The protein is expressed in keratinizing and nonkeratinizing stratified squamous epithelia and in a number of other epithelia. Expression of the protein is upregulated during the terminal differentiation of epidermal keratinocytes in vivo and in culture. Immunogold electron microscopy was used to demonstrate an association of the 195-kD protein with the desmosomal plaque and with keratin filaments in the differentiated layers of the epidermis. Sequence analysis showed that the 195-kD protein is a member of the plakin family of proteins, to which envoplakin, desmoplakin, bullous pemphigoid antigen 1, and plectin belong. Envoplakin and the 195-kD protein coimmunoprecipitate. Analysis of their rod domain sequences suggests that the formation of both homodimers and heterodimers would be energetically favorable. Confocal immunofluorescent microscopy of cultured epidermal keratinocytes revealed that envoplakin and the 195-kD protein form a network radiating from desmosomes, and we speculate that the two proteins may provide a scaffolding onto which the cornified envelope is assembled. We propose to name the 195-kD protein periplakin.

Amino Acid Sequence↗
PubMed2004

Plakin proteins are coordinately cleaved during apoptosis but preferentially through the action of different caspases.

In epithelial cells, cell-cell and cell-matrix junctions, desmosomes and hemidesmosomes, provide anchorage sites for the keratin-intermediate filaments. The plakin proteins desmoplakin (DP), plectin, and periplakin represent intracellular constituents of these adhesion junctions. In staurosporine-treated apoptotic HaCaT cells, DP, plectin, and periplakin became cleaved coordinately with the elimination of keratins 10 and 14, while involucrin, actin, and keratin 18 displayed considerable stability. The caspase inhibitor zVAD-fmk prevented both the cell detachment and protein cleavage, indicating the function of caspases in these events. Closer examination in vitro revealed that while caspases 2 and 4 most efficiently cleaved DP, and plectin served as a target for caspases 3 and 7, periplakin as well as keratins were cleaved by caspase 6. The involvement of multiple caspases in the destruction of epithelial cell integrity ensures the efficient elimination of cytoskeleton, but also provides specificity for selectively targeting individual adhesion molecules.

Amino Acid Chloromethyl Ketones↗
PubMed2002

Binding of protein kinase B to the plakin family member periplakin.

The serine/threonine kinase protein kinase B (PKB/c-Akt) acts downstream of the lipid kinase phosphoinositide 3-kinase (PI3K) and functions as an essential mediator in many growth-factor-induced cellular responses such as cell cycle regulation, cell survival and transcriptional regulation. PI3K activation generates 3'-phosphorylated phosphatidylinositol lipids (PtdIns3P) and PKB activation requires PtdIns3P-dependent membrane translocation and phosphorylation by upstream kinases. However PKB activation and function is also regulated by interaction with other proteins. Here we show binding of PKB to periplakin, a member of the plakin family of cytolinker proteins. Interaction between PKB and periplakin was mapped to part of the pleckstrin homology (PH) domain of PKB, which is probably not involved in lipid binding, and indeed binding to periplakin did not affect PKB activation. We therefore investigated the possibility that periplakin may act as a scaffold or localization signal for PKB. In cells endogenous periplakin localizes to different cellular compartments, including plasma membrane, intermediate filament structures, the nucleus and mitochondria. Overexpression of the C-terminal part of periplakin, encompassing the PKB binding region, results in predominant intermediate filament localization and little nuclear staining. This also resulted in inhibition of nuclear PKB signalling as indicated by inhibition of PKB-dependent Forkhead transcription factor regulation. These results suggest a possible role for periplakin as a localization signal in PKB-mediated signalling.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2006

Asymmetric synthesis of 1,2-dioxolane-3-acetic acids: synthesis and configurational assignment of plakinic acid A.

The first asymmetric synthesis of 1,2-dioxolane-3-acetic acids is reported. Key features include the stereoselective opening of enantiomerically enriched oxetanes by hydrogen peroxide, conversion of the resulting 4-hydroperoxy-2-alkanols to 3-alkoxy-1,2-dioxolanes, and Lewis acid mediated homologation of the latter with a thioester silyl ketene acetal. The approach is modeled on 3,5-dimethyl-5-hexadecyl-1,2-dioxolane-3-acetic acid (1a), an unnamed natural product, and an optimized strategy is applied to the synthesis of four stereoisomers of plakinic acid A (2), allowing a configurational assignment of this incompletely characterized natural product.

Alcohols↗
PubMed2002

The plakin Short Stop and the RhoA GTPase are required for E-cadherin-dependent apical surface remodeling during tracheal tube fusion.

Cells in vascular and other tubular networks require apical polarity in order to contact each other properly and to form lumen. As tracheal branches join together in Drosophila melanogaster embryos, specialized cells at the junction form a new E-cadherin-based contact and assemble an associated track of F-actin and the plakin Short Stop (shot). In these fusion cells, the apical surface determinant Discs Lost (Dlt) is subsequently deposited and new lumen forms along the track. In shot mutant embryos, the fusion cells fail to remodel the initial E-cadherin contact, to make an associated F-actin structure and to form lumenal connections between tracheal branches. Shot binding to F-actin and microtubules is required to rescue these defects. This finding has led us to investigate whether other regulators of the F-actin cytoskeleton similarly affect apical cell surface remodeling and lumen formation. Expression of constitutively active RhoA in all tracheal cells mimics the shot phenotype and affects Shot localization in fusion cells. The dominant negative RhoA phenotype suggests that RhoA controls apical surface formation throughout the trachea. We therefore propose that in fusion cells, Shot may function downstream of RhoA to form E-cadherin-associated cytoskeletal structures that are necessary for apical determinant localization.

Animals↗
PubMed2002

The 'spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families.

Recent studies have characterised a family of giant cytoskeletal crosslinkers encoded by the short stop gene in Drosophila and the dystonin/BPAG1 and MACF1 genes in mammals. We refer to the products of these genes as spectraplakins to highlight the fact that they share features with both the spectrin and plakin superfamilies. These genes produce a variety of large proteins, up to almost 9000 residues long, which can potentially extend 0.4 micro m across a cell. Spectraplakins can interact with all three elements of the cytoskeleton: actin, microtubules and intermediate filaments. The analysis of mutant phenotypes in BPAG1 in mouse and short stop in Drosophila demonstrates that spectraplakins have diverse roles. These include linking the plasma membrane and the cytoskeleton, linking together different elements of the cytoskeleton and organising membrane domains.

Actins↗
PubMed2000

Anti-plakin and desmoglein autoantibodies in a dog with pemphigus vulgaris.

Paraneoplastic pemphigus was suspected in a 14-year-old Labrador retriever because of mucocutaneous erosions, microscopic suprabasal acantholysis, and keratinocyte apoptosis. In this patient, circulating IgG autoantibodies recognized plakin (envoplakin, periplakin) and desmoglein (desmoglein-1 and -3) antigens. Necropsy, however, failed to confirm the concurrent existence of hematopoietic or solid neoplasia. The diagnosis of pemphigus vulgaris therefore was proposed. This study illustrates that such a combination of clinicopathologic lesions and plakin/desmoglein-specific autoantibodies is not restricted to canine paraneoplastic pemphigus but can also be detected in another form of suprabasal pemphigus.

Animals↗