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The BPAG1 locus: Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles.

Leung CL, Zheng M, Prater SM, Liem RK - J. Cell Biol. (2001)

Bottom Line: We have analyzed the BPAG1 locus in detail and found that it encodes different interaction domains that are combined in tissue-specific manners.BPAG1-a is composed of the ABD, the plakin domain, the SR-containing rod domain, and the MTBD.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

ABSTRACT
Bullous pemphigoid antigen 1 (BPAG1) is a member of the plakin family with cytoskeletal linker properties. Mutations in BPAG1 cause sensory neuron degeneration and skin fragility in mice. We have analyzed the BPAG1 locus in detail and found that it encodes different interaction domains that are combined in tissue-specific manners. These domains include an actin-binding domain (ABD), a plakin domain, a coiled coil (CC) rod domain, two different potential intermediate filament-binding domains (IFBDs), a spectrin repeat (SR)-containing rod domain, and a microtubule-binding domain (MTBD). There are at least three major forms of BPAG1: BPAG1-e (302 kD), BPAG1-a (615 kD), and BPAG1-b (834 kD). BPAG1-e has been described previously and consists of the plakin domain, the CC rod domain, and the first IFBD. It is the primary epidermal BPAG1 isoform, and its absence that is the likely cause of skin fragility in mutant mice. BPAG1-a is the major isoform in the nervous system and a homologue of the microtubule actin cross-linking factor, MACF. BPAG1-a is composed of the ABD, the plakin domain, the SR-containing rod domain, and the MTBD. The absence of BPAG1-a is the likely cause of sensory neurodegeneration in mutant mice. 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.

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The genomic structure of BPAG1 and the predicted architecture of BPAG1 isoforms. (A) The structure of the 5′ portion of BPAG1 gene is illustrated. The putative promoters are indicated by arrows. The plakin domain is encoded by 21 exons (black), whereas the CC rod domain and the IFBD1 are each coded by a single exon (light gray). The dark gray boxes represent exons specific for BPAG1-b that contain the IFBD2. Exons and cDNA (hatched boxes) that harbor a stop codon are marked. (B) Schematic representation of the domain structure of BPAG1 isoforms. The names of BPAG1 isoforms, their predicted molecular masses, and the length of their composite cDNAs are indicated. Bold lines underneath the schematic protein drawings represent nested PCR products. The names of individual domains are indicated, except for the EF-hand calcium binding motifs (small gray boxes) and the MT-binding Gas-2–related domain (hatched boxes). The numbers of the amino acids that mark the boundaries of each domain are also shown.
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fig1: The genomic structure of BPAG1 and the predicted architecture of BPAG1 isoforms. (A) The structure of the 5′ portion of BPAG1 gene is illustrated. The putative promoters are indicated by arrows. The plakin domain is encoded by 21 exons (black), whereas the CC rod domain and the IFBD1 are each coded by a single exon (light gray). The dark gray boxes represent exons specific for BPAG1-b that contain the IFBD2. Exons and cDNA (hatched boxes) that harbor a stop codon are marked. (B) Schematic representation of the domain structure of BPAG1 isoforms. The names of BPAG1 isoforms, their predicted molecular masses, and the length of their composite cDNAs are indicated. Bold lines underneath the schematic protein drawings represent nested PCR products. The names of individual domains are indicated, except for the EF-hand calcium binding motifs (small gray boxes) and the MT-binding Gas-2–related domain (hatched boxes). The numbers of the amino acids that mark the boundaries of each domain are also shown.

Mentions: We cloned cDNAs of MACF2 by nested PCR. By sequentially performing PCR on a mouse brain cDNA library with primers specific for four EST clones (GenBank/EMBL/DDBJ accession no. AI526522, AA668029, AA765549, and AI058268) and for the end sequences of the previously amplified PCR products, we obtained three consecutively overlapping cDNAs that spanned ∼9.7 kb of the 3′ coding region of mouse MACF2. The 5′ portion of this composite MACF2 cDNA displayed significant sequence homology to a human genomic bacterial artificial chromosome clone, RP1-61B2 (GenBank/EMBL/DDBJ accession no. AL096710). This bacterial artificial chromosome clone was arbitrarily divided into three segments: the first segment included most of the exons of the BPAG1 gene; the second segment contained a putative exon with an ∼5-kb ORF; and the third segment was made up of many small exons that encoded the SRs of MACF2 (Fig. 1 A).


The BPAG1 locus: Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles.

Leung CL, Zheng M, Prater SM, Liem RK - J. Cell Biol. (2001)

The genomic structure of BPAG1 and the predicted architecture of BPAG1 isoforms. (A) The structure of the 5′ portion of BPAG1 gene is illustrated. The putative promoters are indicated by arrows. The plakin domain is encoded by 21 exons (black), whereas the CC rod domain and the IFBD1 are each coded by a single exon (light gray). The dark gray boxes represent exons specific for BPAG1-b that contain the IFBD2. Exons and cDNA (hatched boxes) that harbor a stop codon are marked. (B) Schematic representation of the domain structure of BPAG1 isoforms. The names of BPAG1 isoforms, their predicted molecular masses, and the length of their composite cDNAs are indicated. Bold lines underneath the schematic protein drawings represent nested PCR products. The names of individual domains are indicated, except for the EF-hand calcium binding motifs (small gray boxes) and the MT-binding Gas-2–related domain (hatched boxes). The numbers of the amino acids that mark the boundaries of each domain are also shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196450&req=5

fig1: The genomic structure of BPAG1 and the predicted architecture of BPAG1 isoforms. (A) The structure of the 5′ portion of BPAG1 gene is illustrated. The putative promoters are indicated by arrows. The plakin domain is encoded by 21 exons (black), whereas the CC rod domain and the IFBD1 are each coded by a single exon (light gray). The dark gray boxes represent exons specific for BPAG1-b that contain the IFBD2. Exons and cDNA (hatched boxes) that harbor a stop codon are marked. (B) Schematic representation of the domain structure of BPAG1 isoforms. The names of BPAG1 isoforms, their predicted molecular masses, and the length of their composite cDNAs are indicated. Bold lines underneath the schematic protein drawings represent nested PCR products. The names of individual domains are indicated, except for the EF-hand calcium binding motifs (small gray boxes) and the MT-binding Gas-2–related domain (hatched boxes). The numbers of the amino acids that mark the boundaries of each domain are also shown.
Mentions: We cloned cDNAs of MACF2 by nested PCR. By sequentially performing PCR on a mouse brain cDNA library with primers specific for four EST clones (GenBank/EMBL/DDBJ accession no. AI526522, AA668029, AA765549, and AI058268) and for the end sequences of the previously amplified PCR products, we obtained three consecutively overlapping cDNAs that spanned ∼9.7 kb of the 3′ coding region of mouse MACF2. The 5′ portion of this composite MACF2 cDNA displayed significant sequence homology to a human genomic bacterial artificial chromosome clone, RP1-61B2 (GenBank/EMBL/DDBJ accession no. AL096710). This bacterial artificial chromosome clone was arbitrarily divided into three segments: the first segment included most of the exons of the BPAG1 gene; the second segment contained a putative exon with an ∼5-kb ORF; and the third segment was made up of many small exons that encoded the SRs of MACF2 (Fig. 1 A).

Bottom Line: We have analyzed the BPAG1 locus in detail and found that it encodes different interaction domains that are combined in tissue-specific manners.BPAG1-a is composed of the ABD, the plakin domain, the SR-containing rod domain, and the MTBD.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

ABSTRACT
Bullous pemphigoid antigen 1 (BPAG1) is a member of the plakin family with cytoskeletal linker properties. Mutations in BPAG1 cause sensory neuron degeneration and skin fragility in mice. We have analyzed the BPAG1 locus in detail and found that it encodes different interaction domains that are combined in tissue-specific manners. These domains include an actin-binding domain (ABD), a plakin domain, a coiled coil (CC) rod domain, two different potential intermediate filament-binding domains (IFBDs), a spectrin repeat (SR)-containing rod domain, and a microtubule-binding domain (MTBD). There are at least three major forms of BPAG1: BPAG1-e (302 kD), BPAG1-a (615 kD), and BPAG1-b (834 kD). BPAG1-e has been described previously and consists of the plakin domain, the CC rod domain, and the first IFBD. It is the primary epidermal BPAG1 isoform, and its absence that is the likely cause of skin fragility in mutant mice. BPAG1-a is the major isoform in the nervous system and a homologue of the microtubule actin cross-linking factor, MACF. BPAG1-a is composed of the ABD, the plakin domain, the SR-containing rod domain, and the MTBD. The absence of BPAG1-a is the likely cause of sensory neurodegeneration in mutant mice. 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.

Show MeSH
Related in: MedlinePlus