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Human Plectin: Organization of the Gene, Sequence Analysis, and Chromosome Localization (8Q24) CHANG-GONG LIU*, CHRISTIAN MAERCKER*, MARIA J

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Human Plectin: Organization of the Gene, Sequence Analysis, and Chromosome Localization (8Q24) CHANG-GONG LIU*, CHRISTIAN MAERCKER*, MARIA J Proc. Natl. Acad. Sci. USA Vol. 93, pp. 4278-4283, April 1996 Biochemistry Human plectin: Organization of the gene, sequence analysis, and chromosome localization (8q24) CHANG-GONG LIU*, CHRISTIAN MAERCKER*, MARIA J. CASTANONt, RUDOLF HAUPTMANNt, AND GERHARD WICHE* *Institute of Biochemistry and Molecular Cell Biology, University of Vienna-Biocenter, 1030 Vienna, Austria; and tErnst Boehringer Institut, 1121 Vienna, Austria Communicated by Gottfried Schatz, Biozentrum der Universitat Basel, Basel, Switzerland, January 2, 1996 (received for review August 28, 1995) ABSTRACT Plectin, a 500-kDa intermediate filament C-terminal globular domain of the molecule (9). The overex- binding protein, has been proposed to provide mechanical pression of plectin mutant proteins containing this site(s) has strength to cells and tissues by acting as a cross-linking a dramatic dominant negative effect on cells, causing the total element of the cytoskeleton. To set the basis for future studies collapse of cytoplasmic IF networks. Based on the combined on gene regulation, tissue-specific expression, and patholog- information available to date, plectin has been proposed to ical conditions involving this protein, we have cloned the play a key role as a versatile cross-linking element of the human plectin gene, determined its coding sequence, and cytoskeleton. Particularly, because of its strategic localization established its genomic organization. The coding sequence at the cytoskeleton-plasma membrane interface, such as in all contains 32 exons that extend over 32 kb ofthe human genome. types of muscle cells; in basal cell layer cells of stratified and Most of the introns reside within a region encoding the single layer epithelia, including epidermis and cornea; and in globular N-terminal domain of the molecule, whereas the cells forming the blood-brain barrier, plectin's functions are entire central rod domain and the entire C-terminal globular expected to contribute to the strengthening of cells toward domain were found to be encoded by single exons of remark- shearing forces or other mechanical stress. However, the able length, >3 kb and >6 kb, respectively. Overall, the precise biological function of the protein is unknown. organization of the human plectin gene was strikingly similar The molecular characterization of human plectin provides a to that of human bullous pemphigoid antigen 1 (BPAG1), new avenue to study the function of this molecule by extending confirming that both proteins belong to the same gene family. these studies to the investigation of its possible role in human Comparison of the deduced protein sequences for human and diseases, whose symptoms correlate with impaired perfor- rat plectin revealed that they were 93% identical. By using mance of cells exposed to great mechanical stress. Pathological fluorescence in situ hybridization, we have mapped the plectin conditions of this kind include muscular dystrophy and blis- gene to the long arm of chromosome 8 within the telomeric tering skin disorders. In this initial study, we report the region. This gene locus (8q24) has previously been implicated exon-intron organization of the human plectin gene, the in the human blistering skin disease epidermolysis bullosa analysis of its coding sequence, and its chromosome localiza- simplex Ogna. Detailed knowledge of the structure of the tion. This information is important for the characterization of plectin gene and its chromosome localization will aid in the mutated human genes, identification of any tissue-specific elucidation of whether this or any other pathological condi- variants, and genetic linkage analysis. tions are linked to alterations in the plectin gene. MATERIALS AND METHODS Plectin, one of the largest polypeptides known (Mr >500,000), Characterization of Human Plectin Clones. Isolation of was identified as a of intermediate originally major component human cDNA clones was performed by several rounds of filament (IF) preparations obtained from cultured cells (1). of two human cDNA libraries in as as structure screening placenta Agtll (one Ultrastructural studies (2) well secondary was a of C. and based on the deduced amino acid of the generous gift Stratowa, EBI, Vienna, Austria, prediction sequence the other was from Clontech), first with two previously char- cloned rat cDNA (3) revealed that the molecule is dumbbell- acterized human plectin probes (3), and then with newly shaped, comprising a long central a-helical coiled-coil rod derived human and a rat subclone. Genomic flanked domains. The dominant structural feature probes plectin by globular clones were isolated from a human placental genomic DNA of the C-terminal domain, six highly homologous repeats library (Stratagene) in two rounds of screening using 32p_- exhibiting in their core a tandemly repeated amino acid labeled human plectin subclones. sequence motif, occur in lesser numbers also in other IF- DNA DNA inserts of human cDNA and as the hemidesmosome-associated Sequencing. plectin associated proteins, such genomic clones were subcloned into Bluescript vectors (Strat- bullous pemphigoid antigen (BPAG1) (4) and desmoplakin, a agene) and sequenced by the dideoxynucleotide termination constituent of desmosomes (5). method (10) using the modified T7 polymerase protocol Unlike IF proteins and other IF-associated proteins, which (United States Biochemical) or an automated DNA sequencer are generally specific to certain cell types and tissues, plectin (Applied Biosystems). On average, each base in the coding is abundantly expressed in many different tissues and cell lines region has been sequenced 6.36 times. All sequence data were (for review, see ref. 6). Furthermore, the protein specifically compiled, assembled, and analyzed using the software pack- binds to a variety of IF proteins, including the nuclear lamina ages LASERGENE (DNASTAR) and DNA STRIDER (11). Splice constituent lamin B, microtubule-associated proteins, and sites and intron-exon boundaries were determined by align- a-spectrin and its nonerythroid analogue, fodrin, major com- ment with the corresponding cDNAs. ponents of the subplasma membrane skeleton (7, 8). Using PCR. Human genomic DNA (Promega) and DNA prepared transient transfection of cultured cells, plectin's binding sites to from the isolated genomic clones was used as template for vimentin and cytokeratin IFs have been localized within the Abbreviations: IF(s), intermediate filament(s); BPAG, bullous pem- The publication costs of this article were defrayed in part by page charge phigoid antigen; FISH, fluorescence in situ hybridization. payment. This article must therefore be hereby marked "advertisement" in The sequences reported in this paper have been deposited in the accordance with 18 U.S.C. §1734 solely to indicate this fact. GenBank data base (accession nos. Z54367 and X59601). 4278 Downloaded by guest on September 28, 2021 Biochemistry: Liu et al. Proc. Natl. Acad. Sci. USA 93 (1996) 4279 PCR. Synthetic oligonucleotide primers complementary to the A flanking exons were used for the DNA amplification. The GN R1 R2 GC reaction conditions were as described by the manufacturer (Perkin-Elmer/Cetus). N--- C Fluorescence in Situ Hybridization (FISH). Metaphase 5'l/////////// //Z3' chromosome spreads were prepared from an Epstein-Barr pCGL25 virus-immortalized pCGL26 lymphoblastic cell line, D282 (ref. 12; pCGL16 originally supplied by C. Gosden and W. Muir, Edinburgh, and pCGL21 kindly provided to us by A. Weith, IMP, Vienna, Austria), HP2 using standard cytogenetic techniques. Pretreatment of slides HP1 pCGL20 for FISH, probe labeling, hybridization, and fluorescence pCGL52 detection of hybridized probes were performed according to pCGL53 published procedures (13) with minor modifications. A 14-kb human genomic clone (HPG9), and a 9-kb clone containing the human MOS protooncogene (kindly provided by F. Propst, B GN R1 R2 GC Vienna-Biocenter) were labeled with biotin-11-dUTP by nick -I// I I translation according to the suppliers protocol (GIBCO/ BRL). For immunofluorescence detection, fluorescein iso- thiocyanate-avidin (Sigma; 5 ,g/ml) in 4 x SSC/0.2% Tween 20 was employed, followed by a 1:200 dilution of monoclonal -----,',//- HPG24, 25 & 29 anti-avidin biotin-conjugated antibody (Sigma). Slides, "----// ------- HPG20 mounted in 0.1% p-phenylenediamine and 0.05% propidium --------------- HPG8 iodide, were viewed using a Bio-Rad MRC-600 confocal HPG9 microscope. Images were processed using the NIH IMAGE software program. FIG. 1. Structural organization of the human plectin gene. (A) The RESULTS schematic drawing on top represents the three major molecular domains of plectin previously identified (3) as (i) the N-terminal Isolation and Characterization of cDNA and Genomic globular domain (horizontal long line), (ii) the a-helical coiled-coil rod Clones. DNA sequencing of two previously described cDNA domain consisting of subdomains Rl and R2 (empty bar), and (iii) the clones, HP1 and HP2, isolated from a Agtll human placenta C-terminal globular domain containing six repeat domains (circles) cDNA expression library using antibodies to rat plectin (3), and a short tail. Underneath, drawn to scale, are the aligned cDNA revealed 94% homology to the corresponding rat sequence on clones isolated from human placenta cDNA libraries. (B) Organiza- the protein level. These two clones, as well as a 2.3-kb probe tion of the human gene and alignment of genomic clones. The 32 exons derived from a 5' rat plectin cDNA clone (C9; ref. 14) and a
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