Differential domain evolution and complex RNA processing in a family of paralogous EPB41 (protein 4.1) genes facilitate expression of diverse tissue-specific isoforms
Section snippets
Protein conservation patterns indicate differential evolutionary rates of individual domains
We assembled composite cDNAs for the four EPB41-related genes, each of which encodes proteins with the general domain structure depicted in the top of Fig. 1A. Other genes with similar names (EPB41L4A, EPB41L4B, EPB41L5, and EPB41LO) contain only the FERM domain and represent a different subclass within the protein 4.1 superfamily. Comparison of the deduced amino acid sequences for the EPB41-related proteins revealed an alternating pattern of highly conserved domains interspersed with poorly
Discussion
This report presents a comparative genomics view of the complex EPB41-related (protein 4.1) family and highlights a number of mechanisms by which these genes can encode a highly diverse set of tissue-specific polypeptides. Through the use of alternative first exons and alternative pre-mRNA splicing, the structure and function of these important proteins can be specifically adapted to the needs of each individual cell type. Differential domain evolution may play a particularly important role,
Assembly of composite EPB41-related cDNAs
The composite transcripts used for mapping to the human genome assembly were derived from the relevant Refseq entries, annotated as needed to include additional exons not represented in Refseq.
EPB41 (protein 4.1R). Refseq NM_004437 includes alternative first exon 1A plus most of the coding exons with the exception of exons 14, 15, 17A, 17B, and 19. The sources of other exons are as follows: exons 1B and 1C, [36]; exons 14 and 15, [32]; exon 17A, [33]; exon 17B, [34]; and exon 19 [9].
EPB41L2
Acknowledgments
This work was supported by National Institutes of Health Grants HL45182, DK32094, and DK56355, and by the Director, Office of Biological and Environmental Research, U.S. Department of Energy under Contract DE-AC03-76SF00098.
References (49)
- et al.
Four paralogous protein 4.1 genes map to distinct chromosomes in mouse and human
Genomics
(1998) - et al.
Molecular and functional characterization of protein 4.1B, a novel member of the protein 4.1 family with high level, focal expression in brain
J. Biol. Chem.
(2000) - et al.
Cloning and characterization of 4.1G (EPB41L2), a new member of the skeletal protein 4.1 (EPB41) gene family
Genomics
(1998) - et al.
Type II brain 4.1 (4.1B/KIAA0987), a member of the protein 4.1 family, is localized to neuronal paranodes
Brain Res. Mol. Brain Res.
(2000) - et al.
Cellular and subcellular localization of a newly identified member of the protein 4.1 family, brain 4.1, in the cerebellum of adult and postnatally developing rats
Brain Res. Dev. Brain Res.
(1999) The spectrin–actin junction of erythrocyte membrane skeletons
Biochim. Biophys. Acta
(1989)- et al.
Association of the type 1 inositol (1,4,5)-trisphosphate receptor with 4.1N protein in neurons
Mol. Cell. Neurosci.
(2003) - et al.
A splicing alteration of 4.1R pre-mRNA generates 2 protein isoforms with distinct assembly to spindle poles in mitotic cells
Blood
(2002) - et al.
Identification of a third Protein 4.1 tumor suppressor, Protein 4.1R, in meningioma pathogenesis
Neurobiol. Dis.
(2003) - et al.
Mechanochemistry of the alternatively spliced spectrin-actin binding domain in membrane skeletal protein 4.1
J. Biol. Chem.
(1993)
Multiple cis elements regulate an alternative splicing event at 4.1R pre-mRNA during erythroid differentiation
Blood
Genomic structure of the locus encoding protein 4.1: structural basis for complex combinational patterns of tissue-specific alternative RNA splicing
J. Biol. Chem.
Organization of the human protein 4.1 genomic locus: new insights into the tissue-specific alternative splicing of the pre-mRNA
Genomics
Cell shape-dependent regulation of protein 4.1 alternative pre-mRNA splicing in mammary epithelial cells
J. Biol. Chem.
Distinct distribution of specific members of protein 4.1 gene family in the mouse nephron
Kidney Int.
Alternative 5′ exons and differential splicing regulate expression of protein 4.1R isoforms with distinct N-termini
Blood
Molecular characterization of a new member of the protein 4.1 family (brain 4.1) in rat brain
Brain Res. Mol. Brain Res.
Tissue- and development-specific alternative RNA splicing regulates expression of multiple isoforms of erythroid membrane protein 4.1
J. Biol. Chem.
Characterization of multiple isoforms of protein 4.1R expressed during erythroid terminal differentiation
Blood
Coupling of transcription with alternative splicing: RNA pol II promoters modulate SF2/ASF and 9G8 effects on an exonic splicing enhancer
Mol. Cell
Transcriptional activators differ in their abilities to control alternative splicing
J. Biol. Chem.
Promoter architecture modulates CFTR exon 9 skipping
J. Biol. Chem.
The 13-kD FK506 binding protein, FKBP13, interacts with a novel homologue of the erythrocyte membrane cytoskeletal protein 4.1
J. Cell Biol.
Restoration of normal membrane stability to unstable protein 4.1-deficient membranes by incorporation of purified protein 4.1
J. Clin. Invest.
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