Alternative Splicing in the Ligand Binding Domain of Mouse ApoE Receptor-2 Produces Receptor Variants Binding Reelin but Not α2-Macroglobulin

LR7/8B and ApoER2 are recently discovered members of the low density lipoprotein (LDL) receptor family. Although structurally different, these two proteins are derived from homologous genes in chicken and man by alternative splicing and contain 7 or 8 LDL receptor ligand-binding repeats. Here we present the cDNA for ApoER2 cloned from mouse brain and describe splice variants in the ligand binding domain of this protein, which are distinct from those present in man and chicken. The cloned cDNA is coding for a receptor with only five LDL receptor ligand-binding repeats,i.e. comprising repeats 1–3, 7, and 8. Reverse transcriptase-polymerase chain reaction analysis of mRNA from murine brain revealed the existence of two additional transcripts. One is lacking repeat 8, and in the other repeat 8 is substituted for by a 13-amino acid insertion with a consensus site for furin cleavage arising from an additional small exon present in the murine gene. None of the transcripts in the mouse, however, contain repeats 4–6. In murine placenta only the form containing repeats 1–3 and 7 and the furin cleavage site is detectable. Analysis of the corresponding region of the murine gene showed the existence of 6 exons coding for a total of 8 ligand binding repeats, with one exon encoding repeats 4–6. Exon trapping experiments demonstrated that this exon is constitutively spliced out in all murine transcripts. Thus, the murineApoER2 gene codes for receptor variants harboring either 4 or 5 binding repeats only. Recombinant expression of the 5-repeat and 4-repeat variants showed that repeats 1–3, 7, and 8 are sufficient for binding of β-very low density lipoprotein and reelin, but not for recognition of α2-macroglobulin, which binds to the avian homologue of ApoER2 harboring 8 ligand binding repeats. LR7/8B and ApoER2 are recently discovered members of the low density lipoprotein (LDL) receptor family. Although structurally different, these two proteins are derived from homologous genes in chicken and man by alternative splicing and contain 7 or 8 LDL receptor ligand-binding repeats. Here we present the cDNA for ApoER2 cloned from mouse brain and describe splice variants in the ligand binding domain of this protein, which are distinct from those present in man and chicken. The cloned cDNA is coding for a receptor with only five LDL receptor ligand-binding repeats,i.e. comprising repeats 1–3, 7, and 8. Reverse transcriptase-polymerase chain reaction analysis of mRNA from murine brain revealed the existence of two additional transcripts. One is lacking repeat 8, and in the other repeat 8 is substituted for by a 13-amino acid insertion with a consensus site for furin cleavage arising from an additional small exon present in the murine gene. None of the transcripts in the mouse, however, contain repeats 4–6. In murine placenta only the form containing repeats 1–3 and 7 and the furin cleavage site is detectable. Analysis of the corresponding region of the murine gene showed the existence of 6 exons coding for a total of 8 ligand binding repeats, with one exon encoding repeats 4–6. Exon trapping experiments demonstrated that this exon is constitutively spliced out in all murine transcripts. Thus, the murineApoER2 gene codes for receptor variants harboring either 4 or 5 binding repeats only. Recombinant expression of the 5-repeat and 4-repeat variants showed that repeats 1–3, 7, and 8 are sufficient for binding of β-very low density lipoprotein and reelin, but not for recognition of α2-macroglobulin, which binds to the avian homologue of ApoER2 harboring 8 ligand binding repeats. low density lipoprotein receptor very LDLR apolipoprotein LDLR relative with 7 or 8 LA repeats apoE receptor 2 receptor-associated protein α2-macroglobulin polymerase chain reaction type A binding repeats type B repeats reverse transcriptase base pair rapid amplification of cDNA ends horseradish peroxidase glutathioneS-transferase The low density lipoprotein receptor (LDLR)1 family consists of a growing number of structurally related composite cell surface receptors with partially overlapping ligand specificity (1Schneider W.J. Nimpf J. Bujo H. Curr. Opin. Lipidol. 1997; 8: 315-319Crossref PubMed Scopus (62) Google Scholar, 2Schneider W.J. Nimpf J. Curr. Opin. Lipidol. 1993; 4: 205-209Crossref Scopus (30) Google Scholar). For example, the LDLR harbors structurally and functionally defined modules, corresponding to distinct exons in the gene (3Schneider W.J. Biochim. Biophys. Acta. 1989; 988: 303-317Crossref PubMed Scopus (57) Google Scholar). These modules are as follows: (i) the “type A-binding repeats” (LA repeats) of ∼40 residues each, displaying a triple disulfide bond-stabilized and negatively charged surface mediating receptor/ligand interactions; (ii) “type B repeats” (EG repeats), also containing six cysteines each; EG repeats are homologous to regions in the epidermal growth factor precursor; (iii) modules of ∼50 residues with a consensus tetrapeptide, Tyr-Trp-Thr-Asp (YWTD); (iv) a so-called “O-linked sugar domain”; (v) a short transmembrane domain of ∼20 amino acids; and (vi) the cytoplasmic region with a signal for receptor internalization via coated pits. LR7/8B (4Novak S. Hiesberger T. Schneider W.J. Nimpf J. J. Biol. Chem. 1996; 271: 11732-11736Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 5Brandes C. Novak S. Stockinger W. Herz J. Schneider W.J. Nimpf J. Genomics. 1997; 42: 185-191Crossref PubMed Scopus (51) Google Scholar) and its human homologue called ApoER2 (6Kim D.-H. Iijima H. Goto K. Sakai J. Ishii H. Kim H.-J. Suzuki H. Kondo H. Saeki S. Yamamoto T. J. Biol. Chem. 1996; 271: 8373-8380Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, 7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar) belong to the close relatives of the LDLR made up of exactly the same domains in the same order as in the LDLR. The occurrence of distinct splice variants adds yet another level of complexity to this family of proteins. LR7/8B expression in chicken is highly restricted to the brain, where the protein resides in large neurons and Purkinje cells, and in cells constituting brain barrier systems such as the epithelial cells of the choroid plexus and the arachnoidea and the endothelium of blood vessels (8Stockinger W. Hengstschläger-Ottnad E. Novak S. Matus A. Hüttinger M. Bauer J. Lassmann H. Schneider W.J. Nimpf J. J. Biol. Chem. 1998; 273: 32213-32221Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The finding that chicken LR8B acts as receptor for α2-macroglobulin (8Stockinger W. Hengstschläger-Ottnad E. Novak S. Matus A. Hüttinger M. Bauer J. Lassmann H. Schneider W.J. Nimpf J. J. Biol. Chem. 1998; 273: 32213-32221Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar) suggests a role in the clearance of α2-macroglobulin-proteinase complexes from the cerebrospinal fluid. Ligand binding studies with two splice variants of human ApoER2 demonstrated high affinity of the receptor to β-VLDL, indicating that in mammals the receptor might be involved in apoE-mediated transport processes in the brain as well (7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). This is an interesting aspect because a of the gene and the of W.J. 1996; PubMed Scopus Google Scholar). in the splice of ApoER2 and Stockinger W. Schneider W.J. Nimpf J. PubMed Scopus (57) Google Scholar). of the gene or in with that for the receptor gene revealed a of receptors brain M. M. Hiesberger T. J. Stockinger W. Nimpf J. Herz J. Full Text Full Text PDF PubMed Scopus Google Scholar). of ApoER2 and receptor to an of and of This is from that in either a in the gene or in the gene Full Text Full Text PDF PubMed Scopus Google Scholar, T. 1998; PubMed Scopus Google Scholar, Curr. Opin. PubMed Scopus Google Scholar). ApoER2 and receptor reelin, which is by cells M. T. Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. A. Herz J. Full Text Full Text PDF PubMed Scopus Google and with receptors K. M. T. Full Text Full Text PDF PubMed Scopus Google Scholar) S. Full Text Full Text PDF PubMed Scopus Google which as for to the signal the protein which with the cytoplasmic domains of and Biol. PubMed Scopus Google Scholar, M. Herz J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google PubMed Scopus Google Scholar, Y. Curr. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). These that ApoER2 and receptor the signal a via to the cell for the of neurons brain In with and other members of the receptor family in the of other proteins with the cytoplasmic domains of the that be of an of M. M. J. Stockinger W. Nimpf J. Herz J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, W. C. M. M. Herz J. Schneider W.J. Nimpf J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Here we present the cDNA and the of the mouse gene and that splicing in the ligand binding domain receptor variants that are distinct from those in chicken and is and is brain The of the mouse cDNA for cloned by the cDNA amplification to the and cDNA from 5 of and the by the in two of with the in an to the The in the from a cDNA (4Novak S. Hiesberger T. Schneider W.J. Nimpf J. J. Biol. Chem. 1996; 271: 11732-11736Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). The which in of The with and in additional of the from of brain and placenta from and total chicken brain from from of total the mRNA to the cDNA with of and Reverse of the cDNA for in the of 2 of polymerase and of the a are as follows: 5 and for The of the to the in mouse mouse mouse mouse mouse mouse chicken 7, chicken 8, by from the the and the from and by analysis and A mouse by the and are as follows: 2 for of a derived from exon (EG repeat these from from the to an additional the with and site of by two pair the and the of the ligand binding The and The of the gene the ligand binding domain of the receptor by derived from the with the and and and and and and from the the the and For the exon two One the exon coding for repeats of the and of the to For 5 cloned in of the exon in The 5 harboring two one for repeat 2 and the other for repeats 4–6. This made by the of 5 and in the of of cells and cells a cells and mRNA the from of mRNA and of and the cDNA by the exon of the cDNA reaction two from the exon 2 and and of the of a and LR8B and mouse and in the human cell The cDNA of mouse and by a cDNA for the mouse protein (4Novak S. Hiesberger T. Schneider W.J. Nimpf J. J. Biol. Chem. 1996; 271: 11732-11736Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar) with the derived from mouse brain cDNA with and via an The of the reaction with containing repeats 1–3, 7, and 8 and repeats 1–3 and 7 a cloned and The cDNA cloned the expression In order to the containing 4 repeats and 5 repeats out from the via an and the site in the of and cloned the containing the of the The for expression of chicken LR8B in cells (8Stockinger W. Hengstschläger-Ottnad E. Novak S. Matus A. Hüttinger M. Bauer J. Lassmann H. Schneider W.J. Nimpf J. J. Biol. Chem. 1998; 273: 32213-32221Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). of the cells to the by the of to the cell from cells or as for chicken K. Nimpf J. Schneider W.J. J. Biol. Chem. 1989; Full Text PDF PubMed Google Scholar). to and as T. M. Novak S. Bujo H. M. Hüttinger M. Schneider W.J. Nimpf J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The the cytoplasmic domains of chicken LR8B (8Stockinger W. Hengstschläger-Ottnad E. Novak S. Matus A. Hüttinger M. Bauer J. Lassmann H. Schneider W.J. Nimpf J. J. Biol. Chem. 1998; 273: 32213-32221Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar) and mouse ApoER2 W. C. M. M. Herz J. Schneider W.J. Nimpf J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) are in the from the of a for S. A. PubMed Scopus Google Scholar) and with by the as K. Nimpf J. Schneider W.J. J. Biol. Chem. 1989; Full Text PDF PubMed Google Scholar). is in of protein that by a as W.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). from chicken as M. Schneider W.J. Nimpf J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to the number to of complexes as M. Schneider W.J. Nimpf J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of by by the by J. Biol. Chem. Full Text PDF PubMed Google Scholar). Recombinant human as a glutathioneS-transferase protein a expression in J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of by and cells to the for of LDL PubMed Scopus Google Scholar). In cells in and to a with cells with containing ligand the for the cells by of of and for The in the with a and the protein by analysis and in for cells and and cells and in and with from cells as M. T. Full Text Full Text PDF PubMed Scopus Google Scholar). In cells with 7 of the The the with a 2 the and for of For ApoER2 cells with of and the cells with of and with of the 4 for 4 in the or of or to a of The cells with of and with containing and the cell for of the a to as T. M. A. Herz J. Full Text Full Text PDF PubMed Scopus Google Scholar). The for with by a of as a a of The an binding to splice variants of the receptor by a by Hiesberger T. M. A. Herz J. Full Text Full Text PDF PubMed Scopus Google Scholar). For this coding for the ligand binding domains of and by the as and to the human domain as T. M. A. Herz J. Full Text Full Text PDF PubMed Scopus Google Scholar) in and Recombinant proteins in cells, and the proteins of cell to as The with of from cells in the of or or for 4 4 of as T. M. A. Herz J. Full Text Full Text PDF PubMed Scopus Google Scholar) as and to as The of proteins present the by an we the cDNA of chicken we also the amino acid derived from a cDNA for the corresponding murine homologue (4Novak S. Hiesberger T. Schneider W.J. Nimpf J. J. Biol. Chem. 1996; 271: 11732-11736Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). The of that cDNA defined the of the repeat of the mouse this for we to this to repeat number 7 of a mouse of LR7/8B that repeat 8 to splicing C. Novak S. Stockinger W. Herz J. Schneider W.J. Nimpf J. Genomics. 1997; 42: 185-191Crossref PubMed Scopus (51) Google Scholar). two of we the cDNA for mouse ApoER2 the murine receptor to be a highly family of proteins to alternative splicing we to the murine protein as as for the human protein by Yamamoto and (6Kim D.-H. Iijima H. Goto K. Sakai J. Ishii H. Kim H.-J. Suzuki H. Kondo H. Saeki S. Yamamoto T. J. Biol. Chem. 1996; 271: 8373-8380Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar). to the of J. PubMed Scopus Google we the cleavage site for the signal to amino a receptor in which the LA repeat is 7 amino that of human and 8 amino that of chicken the murine cDNA codes for a receptor harboring only 5 LA repeats. with human and chicken that repeats are from this such a for human ApoER2 (7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). the cloned murine the repeat but not a 13-amino acid insertion that harbors a furin consensus cleavage site its transcripts containing such an insertion in man and but not in chicken C. Novak S. Stockinger W. Herz J. Schneider W.J. Nimpf J. Genomics. 1997; 42: 185-191Crossref PubMed Scopus (51) Google Scholar). these that the ligand binding domain of murine might be to alternative splicing a highly of this in in close we the splice variants in brain and the of ApoER2 expression in the mouse by experiments of the region repeat 7 and the of the EG repeats and the of repeats in 2 in mouse brain distinct variants are These transcripts contain in to repeats 1–3 the (i) either repeats 7 and 8 (ii) only repeat 7 with a 13-amino acid insertion a consensus furin cleavage site or (iii) repeat 7 only In brain however, the large containing repeat 8 is This a splice from that in the brain 2 In mouse placenta a with a of is present 2 this out to be the coding for the receptor containing the insertion with the furin site and lacking repeat 8. the cleavage this site the corresponding protein be a receptor with from those of the variants present in the a pair repeats and the only mRNA either from brain or placenta a of 2 that the cDNA to the corresponding region of the cDNA in lacking repeats 4–6. we the same analysis with a pair chicken brain mRNA as in the only a of and is derived from a containing these LA repeats. exactly these repeats are for by a exon in the human gene (7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google we the corresponding exon from the mouse gene or is from the transcripts by alternative Thus, we the of the murine gene which codes for the ligand binding domain of the in the region of of the murine gene cloned by a of of a and of by in the regions of the gene. The gene is in the same as that for human (7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). In the exon encoding the LA repeats is present in the murine the corresponding cDNA is in C. the coding for repeats from we to another for the of transcripts containing this exon in brain and A corresponding to this exon 5 and to corresponding transcripts by in 2 the with a of only the as but not with cDNA derived from either brain or This that this exon is from transcripts in demonstrated that in splice splicing Nimpf J. Schneider W.J. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). Thus, the of exon 5 with the consensus for such regions Analysis of and Scholar). splice the consensus in that the site the which is and the site a which a the of the corresponding are in the are the murine and the human gene the of the gene and the of the is not this exon is spliced out constitutively from the transcripts in but only in man (7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). in a where splicing of ApoER2 in and the corresponding exon in all human brain Stockinger W. Schneider W.J. Nimpf J. PubMed Scopus (57) Google Scholar). the we cloned a containing the exon coding for repeat and of the and the exon 4 we this with another harboring the exon coding for repeat 2 cells 4 a of from that by the of these to be derived from the exons present in the however, a with a of containing a cDNA made up of the exons present in the and the exon coding for repeat The exon for repeats from the indicating that this is not as exon in this very interesting of the murine gene is the that the short insertion of amino a consensus furin cleavage present in splice variants of ApoER2 C. Novak S. Stockinger W. Herz J. Schneider W.J. Nimpf J. Genomics. 1997; 42: 185-191Crossref PubMed Scopus (51) Google is by a small exon and is not by the of an alternative as might be for such a small The exon is those for LA repeat 8 and EG repeat of this region are in a homologous insertion is also present in variants of human ApoER2 C. Novak S. Stockinger W. Herz J. Schneider W.J. Nimpf J. Genomics. 1997; 42: 185-191Crossref PubMed Scopus (51) Google we that in the human gene a corresponding exon is present in 6 to 7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). the of repeats in the murine receptor which to the expression of receptor variants with either 4 or 5 ligand binding repeats in distinct ligand we these and in cells, for and and the with those with the chicken containing the of 8 ligand binding repeats The in a with from cells murine and chicken LR8B for the murine proteins from in this cell for the of these receptors to with we a binding and internalization (8Stockinger W. Hengstschläger-Ottnad E. Novak S. Matus A. Hüttinger M. Bauer J. Lassmann H. Schneider W.J. Nimpf J. J. Biol. Chem. 1998; 273: 32213-32221Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). demonstrated in all receptor variants with high affinity of for of for of 8 for This is not a human of ApoER2 harboring only binding repeats to (7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). the affinity for with the of binding repeats. very interesting to that mouse and in to LR8B which binds with high affinity of and (8Stockinger W. Hengstschläger-Ottnad E. Novak S. Matus A. Hüttinger M. Bauer J. Lassmann H. Schneider W.J. Nimpf J. J. Biol. Chem. 1998; 273: 32213-32221Abstract Full Text Full Text PDF PubMed Scopus (63) Google The small of and binding to cells is to low expression of protein by these cells (8Stockinger W. Hengstschläger-Ottnad E. Novak S. Matus A. Hüttinger M. Bauer J. Lassmann H. Schneider W.J. Nimpf J. J. Biol. Chem. 1998; 273: 32213-32221Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). an of is interesting that the of binding repeats by splicing of the corresponding exon in the of the receptor to a of 8 ligand binding repeats for recognition of as by the that the chicken homologue of the 8 ligand binding repeats and binds with high affinity (8Stockinger W. Hengstschläger-Ottnad E. Novak S. Matus A. Hüttinger M. Bauer J. Lassmann H. Schneider W.J. Nimpf J. J. Biol. Chem. 1998; 273: 32213-32221Abstract Full Text Full Text PDF PubMed Scopus (63) Google the LDLR harboring repeats recently that one of the murine variants acts as receptor for M. T. Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. A. Herz J. Full Text Full Text PDF PubMed Scopus Google and as demonstrated 7, expression of the 4-repeat and 5-repeat variants in the mouse brain is highly we and binding to receptor binding with two one cells M. T. Full Text Full Text PDF PubMed Scopus Google Scholar) and the other receptor as recently T. M. A. Herz J. Full Text Full Text PDF PubMed Scopus Google Scholar). demonstrated in cells either or of by of to receptor variants is by and This by the that ApoER2 receptor harboring either 4 or 5 binding repeats with 7 binding is by an of or by The is in which all transcripts in the ligand binding domain of the receptor in In where the expression of LR7/8B in brain, only two distinct variants harboring 7 or 8 repeats the mRNA the furin cleavage which in man and mouse, is the corresponding region of the chicken gene not to and well be that this exon is constitutively spliced out in chicken transcripts. the the corresponding exon in mammals be The mouse, as transcripts in the ligand binding are two to the transcripts in chicken. of the transcripts repeats which are present a exon analysis suggests that this exon is constitutively by splicing out in in is an additional small exon that for LA repeat 8, to a harboring a furin consensus cleavage site the of the ligand binding this is the only one in that of the splice are The in man is not as of the transcripts contain repeat 8, and analysis of the human gene suggests that the corresponding exon might (6Kim D.-H. Iijima H. Goto K. Sakai J. Ishii H. Kim H.-J. Suzuki H. Kondo H. Saeki S. Yamamoto T. J. Biol. Chem. 1996; 271: 8373-8380Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, 7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). this exon to be present in the human but a in the site this exon to be constitutively H.-J. Kim D.-H. Magoori K. Saeki S. Yamamoto T.T. J. 1998; PubMed Scopus Google Scholar). In to the mouse a corresponding exon coding for the site insertion C. Novak S. Stockinger W. Herz J. Schneider W.J. Nimpf J. Genomics. 1997; 42: 185-191Crossref PubMed Scopus (51) Google Scholar) is present in the corresponding region of the human gene. In to the mouse variants a receptor containing only repeats 1–3 to be present in (7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). the of exon coding for repeats not be in a and Stockinger W. Schneider W.J. Nimpf J. PubMed Scopus (57) Google Scholar). that all human splice variants are to with affinity (6Kim D.-H. Iijima H. Goto K. Sakai J. Ishii H. Kim H.-J. Suzuki H. Kondo H. Saeki S. Yamamoto T. J. Biol. Chem. 1996; 271: 8373-8380Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, 7Kim D.-H. Magoori K. Inoue T.R. Mao C.C. Kim H.-J. Suzuki H. Fujita T. Endo Y. Saeki S. Yamamoto T.T. J. Biol. Chem. 1997; 272: 8498-8504Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Thus, is not that murine and with high the that mouse ApoER2 not is interesting from an of that the chicken homologue a of the of binding to mouse ApoER2 is not the a of 8 ligand binding repeats in one domain protein, chicken chicken ApoER2 its to but other from to These the to be as a receptor and the to with proteins and by an insertion in the cytoplasmic of the receptor W. C. M. M. Herz J. Schneider W.J. Nimpf J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). this for the that murine ApoER2 variants containing either 4 or 5 LA repeats that the expression of the variants is highly brain might be that other in the brain which ApoER2 variants the or mediating a the of LA repeats in LDLR relatives ligand binding the splicing in and ApoER2 gene might in a of its in and the of and for the of the and for the expression