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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4404-4414
Characterization of Multiple Isoforms of Protein 4.1R Expressed
During Erythroid Terminal Differentiation
P. Gascard,
G. Lee,
L. Coulombel,
I. Auffray,
M. Lum,
M. Parra,
J.G. Conboy,
N. Mohandas, and
J.A. Chasis
From the Life Science Division, Biophysics and Biomolecular Structure
Department, Lawrence Berkeley National Laboratory, Berkeley, CA; and
the Laboratoire Hématopoïèse et Cellules Souches,
Villejuif, France.
In erythrocytes, 80-kD protein 4.1R regulates critical
membrane properties of deformability and mechanical strength. However, previously obtained data suggest that multiple isoforms of protein 4.1, generated by alternative pre-mRNA splicing, are expressed during
erythroid differentiation. Erythroid precursors use two splice acceptor
sites at the 5 end of exon 2, thereby generating two populations
of 4.1 RNA: one that includes an upstream AUG-1 in exon 2 and
encodes high molecular weight isoforms, and another that skips AUG-1 in
exon 2 and encodes 4.1 by initiation at a downstream AUG-2 in
exon 4. To begin an analysis of the complex picture of protein 4.1R
expression and function during erythropoiesis, we determined the number
and primary structure of 4.1R isoforms expressed in erythroblasts. We
used reverse-transcription polymerase chain reaction to amplify and
clone full-length coding domains from the population of 4.1R cDNA
containing AUG-1 and the population excluding AUG-1. We observed an
impressive repertoire of 4.1R isoforms that included 7 major and 11 minor splice variants, thus providing the first definitive
characterization of 4.1R primary structures in a single-cell lineage.
4.1R isoforms, transfected into COS-7 cells, distributed to the
nucleus, cytoplasm, plasma membrane, and apparent centrosome. We
confirmed previous studies showing that inclusion of exon 16 was
essential for efficient nuclear localization. Unexpectedly,
immunochemical analysis of COS-7 cells transfected with an isoform
lacking both AUG-1 and AUG-2 documented that a previously unidentified
downstream translation initiation codon located in exon 8 can regulate
expression of 4.1R. We speculate that the repertoire of primary
structure of 4.1R dictates its distinct binding partners and functions
during erythropoiesis.
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