Key points are not available for this paper at this time.
Normal cell development depends to a large part on multifunctional proteins that have evolved by recombination of proven modular elements. We now have discovered and characterized in rabbit such a multi-domain protein, and classify it as novel member of the low density lipoprotein (LDL) receptor gene family. The extracellular portion of the ~250-kDa membrane protein, termed LR11, contains a cluster of 11 LDL receptor ligand binding repeats, a group of 5 LDL receptor “YWTD” repeats, a large hexarepeat domain of structural elements found in neural cell adhesion molecules, and a domain with similarity to a yeast receptor for vacuolar protein sorting, VPS10. The cytoplasmic domain exhibits features typical of endocytosis-competent coated-pit receptors. The mosaic, and presumably multifunctional, receptor is expressed abundantly in brain, in particular the hippocampus, dentate gyrus, and cerebral cortex, and is present at significant levels in liver, adrenal glands, and testis. Western blotting of tissues and ligand blotting of LR11-transfected cells demonstrated that the novel protein binds apolipoprotein E-containing lipoproteins. In contrast to the LDL receptor, hepatic expression of LR11 is unaffected by hyperlipidemia. The identification of this highly conserved and superbly complex protein offers the opportunity to gain new insights into the emergence of multifunctional mosaic proteins akin to the ever expanding LDL receptor gene family. Normal cell development depends to a large part on multifunctional proteins that have evolved by recombination of proven modular elements. We now have discovered and characterized in rabbit such a multi-domain protein, and classify it as novel member of the low density lipoprotein (LDL) receptor gene family. The extracellular portion of the ~250-kDa membrane protein, termed LR11, contains a cluster of 11 LDL receptor ligand binding repeats, a group of 5 LDL receptor “YWTD” repeats, a large hexarepeat domain of structural elements found in neural cell adhesion molecules, and a domain with similarity to a yeast receptor for vacuolar protein sorting, VPS10. The cytoplasmic domain exhibits features typical of endocytosis-competent coated-pit receptors. The mosaic, and presumably multifunctional, receptor is expressed abundantly in brain, in particular the hippocampus, dentate gyrus, and cerebral cortex, and is present at significant levels in liver, adrenal glands, and testis. Western blotting of tissues and ligand blotting of LR11-transfected cells demonstrated that the novel protein binds apolipoprotein E-containing lipoproteins. In contrast to the LDL receptor, hepatic expression of LR11 is unaffected by hyperlipidemia. The identification of this highly conserved and superbly complex protein offers the opportunity to gain new insights into the emergence of multifunctional mosaic proteins akin to the ever expanding LDL receptor gene family. INTRODUCTIONThe discovery of the LDL receptor (LDLR) 1The abbreviations used are: LDLRlow density lipoprotein receptorLR11LDLR relative with 11 binding repeatsLR8(B)LDLR relative with eight binding repeats (B)apoapolipoproteinbpbase pair(s)β-VLDLβ-migrating very low density lipoproteinLRPLDLR related protein/α2-macroglobin receptorEGFepidermal growth factorCHOChinese hamster ovaryPAGEpolyacrylamide gel electrophoresisWHHLWatanabe heritable hyperlipidemicFNIIIfibronectin type III. and its functional and genetic characterization were hallmarks in research on lipoprotein transport pathways and led to the molecular delineation of the common hereditary disease, familial hypercholesterolemia (Brown and Goldstein, 7Brown M.S. Goldstein J.L. Science. 1986; 232: 34-47Google Scholar). In contrast to the clarity of our understanding of LDLR function, the physiological roles of new LDLR homologues, which have been identified in the past decade and form the ever expanding LDLR gene family, are far from being established. Their apparently much more diverse functions are indicated by a wide range of possible ligands, which include spent, biologically inactive and/or unwanted plasma carrier complexes and complex proteins, certain toxins, yolk precursors, as well as circulating plasma lipoproteins (reviewed in Krieger and Herz (35Krieger M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Google Scholar), Schneider and Nimpf (61Schneider W.J. Nimpf J. Curr. Opin. Lipidol. 1993; 4: 205-209Google Scholar), Moestrup (44Moestrup S.K. Biochim. Biophys. Acta. 1994; 1197: 197-213Google Scholar), and Schneider (62Schneider W.J. Curr. Opin. Lipidol. 1995; 6: 92-96Google Scholar)). The bewildering array of ligands they can bind, at least in vitro, is probably due to their highly variable content of different numbers and combinations of common structural elements.To date, these identified common structural modules are (i) the so-called “LDLR ligand binding repeats,” complement-type domains consisting of ~40 residues displaying a triple-disulfide bond-stabilized negatively charged surface; (ii) epidermal growth factor precursor-type repeats, also containing six cysteines each; (iii) modules of ~50 residues each, most often in groups of five, with a consensus tetrapeptide, Tyr-Trp-Thr-Asp (LDLR “YWTD” repeats); and (iv) in the cytoplasmic region, signals for receptor internalization via coated pits, containing the consensus tetrapeptide Asn-Pro-Xaa-Tyr (NPXY) (Chen et al., 11Chen W.-J. Goldstein J.L. Brown M.S. J. Biol. Chem. 1990; 265: 3116-3123Google Scholar).The best characterized binding domain is that of the LDLR, which consists of seven complement-type repeats and recognizes apolipoprotein (apo) B and apoE (Russel et al., 1989). LDLR family members harbor from 1 to 4 clusters with varying numbers of ligand binding repeats. To date, the family includes in addition to the LDLR, the very low density lipoprotein (VLDL) receptor (Takahashi et al., 67Takahashi S. Kawarabayasi Y. Nakai T. Sakai J. Yamamoto T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9252-9256Google Scholar; Bujo et al., 8Bujo H. Hermann M. Kaderli M.O. Jacobsen L. Sugawara S. Nimpf J. Yamamoto T. Schneider W.J. EMBO J. 1994; 13: 5165-5175Google Scholar), Drosophila yolkless (Yl) (Schonbaum et al., 63Schonbaum C.P. Lee S. Mahowald A.P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1485-1489Google Scholar), LDLR related protein/α2-macroglobulin receptor (LRP) (Herz et al. 20Herz J. Hamann U. Rogne S. Myklebost O. Gausepohl H. Stanley K.K. EMBO J. 1988; 7: 4119-4127Google Scholar), the Caenorhabditis elegans LRP-like gene (Yochem and Greenwald, 75Yochem J. Greenwald I. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4572-4576Google Scholar), and gp330/megalin (Saito et al., 58Saito A. Pietromonaco S. Loo A.K.-C. Farquhar M.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9725-9729Google Scholar). Extensive studies on the ligand specificities of these proteins have shown that they likely are multifunctional receptors, cellular uptake of plasma lipoproteins being just one of their tasks. For instance, one of the functionally best documented receptor, the chicken oocytes' eight ligand binding repeat receptor, termed LR8 (Bujo et al., 10Bujo H. Lindstedt K.A. Hermann M. Dalmau L.M. Nimpf J. Schneider W.J. J. Biol. Chem. 1995; 270: 23546-23551Google Scholar), takes up the yolk precursors, riboflavin binding protein (Mac Lachlan et al., 37Mac Lachlan I. Nimpf J. Schneider W.J. J. Biol. Chem. 1994; 269: 24127-24132Google Scholar), α2-macroglobulin (Jacobsen et al., 26Jacobsen L. Hermann M. Vieira P.M. Schneider W.J. Nimpf J. J. Biol. Chem. 1995; 270: 6468-6475Google Scholar), VLDL, and vitellogenin (Bujo et al., 8Bujo H. Hermann M. Kaderli M.O. Jacobsen L. Sugawara S. Nimpf J. Yamamoto T. Schneider W.J. EMBO J. 1994; 13: 5165-5175Google Scholar). Chicken LR8 also recognizes the iron-binding protein, lactoferrin (Hiesberger et al., 21Hiesberger T. Hermann M. Jacobsen L. Novak S. Hodits R.A. Bujo H. Meilinger M. Hüttinger M. Schneider W.J. Nimpf J. J. Biol. Chem. 1995; 270: 18219-18226Google Scholar). Importantly, a mutation in LR8 (ovr−) lends genetic proof to LR8's function as yolk precursor transporter: it causes female sterility (non-laying) and severe hyperlipidemia with associated premature atherosclerosis (Bujo et al., 9Bujo H. Yamamoto T. Hayashi K. Hermann M. Nimpf J. Schneider W.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9905-9909Google Scholar).Without question, the ligand binding repeats are the most characteristic structural modules of the LDLR gene family. However, in a wide variety of species these subdomains have been shuffled into proteins whose functions seem to be unrelated to lipoprotein metabolism. Among these are several proteins of the blood complement system (Haefliger et al. (19Haefliger J.-A. Tschopp J. Nardelli D. Wahli W. Kocher H.-P. Tosi M. Stanley K.K. Biochemistry. 1987; 26: 3551-3556Google Scholar), reviewed in Hobbs et al. (22Hobbs H.H. Russell D.W. Brown M.S. Goldstein J.L. Annu. Rev. Genet. 1990; 24: 133-170Google Scholar)); a basement membrane heparan sulfate proteoglycan, perlecan (Noonan et al., 47Noonan D.M. Fulle A. Valente P. Cai S. Horigan E. Sasaki M. Yamada Y. Hassell J.R. J. Biol. Chem. 1991; 266: 22939-22947Google Scholar; Kallunki and Tryggvason, 28Kallunki P. Tryggvason K. J. Cell Biol. 1992; 116: 559-571Google Scholar); a rat apical early endosomal glycoprotein (Speelman et al., 64Speelman B.A. Allen K. Grounds T.L. Neutra M.R. Kirchhausen T. Wilson J.M. J. Biol. Chem. 1995; 270: 1583-1588Google Scholar); a cortical granule protein in sea urchin (Wessel, 72Wessel G.M. Dev. Biol. 1995; 167: 388-397Google Scholar); a linker chain of earthworm hemoglobin (Suzuki and Riggs, 66Suzuki T. Riggs A.F. J. Biol. Chem. 1993; 268: 13548-13555Google Scholar); a G-protein coupled receptor in the ganglion of Lymnaea (Tensen et al., 70Tensen C.P. van Kesteren E.R. Planta R.J. Cox K.J.A. Burke J.F. van Heerikhuizen H. Vreugdenhil E. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 4816-4820Google Scholar); and a chicken rous sarcoma virus receptor (Bates et al., 4Bates P. Young J.A.T. Varmus H.E. Cell. 1993; 74: 1043-1051Google Scholar). Thus, the complement-type repeats in the LDLR are shared by a number of proteins that participate in diverse biological processes. For instance, the occurrence of complement-type repeats together with EGF precursor homology domain(s) in some extracellular matrix proteins, such as perlecan, suggests that certain family members might be involved in cell growth and cellular attachment.We now have discovered a novel and unusually complex member of the LDLR gene family from rabbit. The predominant domain of the type I membrane protein consists of a cluster of 11 LDLR ligand binding repeats; according to our preferred nomenclature which avoids confusing and/or unproven ligand designations (Bujo et al., 10Bujo H. Lindstedt K.A. Hermann M. Dalmau L.M. Nimpf J. Schneider W.J. J. Biol. Chem. 1995; 270: 23546-23551Google Scholar), the new receptor is termed LR11. It also contains sequences highly homologous to a yeast receptor for vacuolar protein sorting, and to cellular adhesion molecules. Highly expressed in brain, LR11 and a 130-kDa receptor, LR8B (Novak et al., 49Novak S. Hiesberger T. Schneider W.J. Nimpf J. J. Biol. Chem. 1996; 271: 11732-11736Google Scholar) are proposed to be members of a hitherto unknown branch of the LDLR gene family which participate in physiological and structural elements the LDLR family are members identified far are of that are up of elements found in the LDLR in which the complement-type repeats a portion to the It is that the wide variety of ligands that with LDLR family members via these complement-type repeats; on the functional of protein domains be from in which and elements are present in novel In the present have identified the of such a gene in LR11, which is a mosaic protein containing several structural elements far found in LDLR gene family elements that LR11 in the LDLR gene family, domains and are in the of the and they are by a hitherto unknown domain containing by precursor repeats (Herz et al., 20Herz J. Hamann U. Rogne S. Myklebost O. Gausepohl H. Stanley K.K. EMBO J. 1988; 7: 4119-4127Google Scholar) LDLR family members to To our et al., S. J. Cell Biol. 1988; Scholar; et al., K. M. L. Yamada Y. T. D. J. Scholar) and the protein et al., Cell. 1990; Scholar) are the proteins with repeats that the typical repeats. In a of basement the repeats are involved in binding to protein in the basement et al., U. M. D. H. K. T. J. EMBO J. 1991; Scholar). In the for binding to is to a with cysteines et al., U. E. K. K. M. Yamada Y. EMBO J. 1993; Scholar). the that LR11 via domain with cell groups of repeats in have been found far and from the ligand binding repeat cluster in The of the repeats at the of the LR11 binding repeat cluster on the one domain and on the that modules are conserved they function as (Herz et al., 20Herz J. Hamann U. Rogne S. Myklebost O. Gausepohl H. Stanley K.K. EMBO J. 1988; 7: 4119-4127Google Scholar), the elegans (Yochem and Greenwald, 75Yochem J. Greenwald I. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4572-4576Google Scholar), and gp330/megalin (Saito et al., 58Saito A. Pietromonaco S. Loo A.K.-C. Farquhar M.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9725-9729Google Scholar) are the proteins that clusters of 11 complement-type repeats. In the clusters of these receptors, certain repeats are from by et al., Goldstein J.L. Brown M.S. D.W. Science. Scholar). LR11 to a typical linker a residues repeats and are also the features of domain which consists of modules as in et al., K. K. EMBO J. 4: Scholar). repeats in LR11 are to the repeats in and its number of extracellular matrix proteins and repeats, neural cell adhesion molecules, receptor family and several receptor and et al., R.A. A. Cell. Biol. 1991; Scholar). The of these repeats in cell adhesion and for cell growth and suggests a of LR11 in domain to our homologous sequences in It is that the rabbit LR11 protein in this domain as this is also found in and et al., M. H. D. K. M. 1988; Scholar; et al., M. S. M. H. P. J. Cell Biol. 1995; Scholar). The of structural features of neural adhesion molecules, together with the expression of the LR11 in brain, are with of LR11 in adhesion and/or of as for and and Cell Biol. 1992; the cytoplasmic LR11 a internalization highly of the the common internalization of LDLR gene family members (Chen et al., 11Chen W.-J. Goldstein J.L. Brown M.S. J. Biol. Chem. 1990; 265: 3116-3123Google Scholar). The and conserved in LR11, have been to be for the of a for internalization (Chen et al., 11Chen W.-J. Goldstein J.L. Brown M.S. J. Biol. Chem. 1990; 265: 3116-3123Google Scholar; and A. L.M. Cell. 1991; Scholar). the in LR11 is to that in the receptor et al. M.R. K. J. Biol. Chem. 1990; 265: Scholar) and and M.G. J. Biol. Chem. 1994; 269: Scholar) that for internalization of via signals are more in the cytoplasmic of the of roles in the and proteins et al., J. Cell Biol. 1995; Scholar; et al., J. J. Biol. Chem. 1995; 270: Scholar). studies are to the of the consensus in LR11, the characteristic together with clusters of charged residues in the cytoplasmic domain also found in LDLR gene family members that the LR11 protein is endocytosis-competent negatively charged in with a shown to be for of the LDLR et al., K. W. I. Cell. 1992; Scholar), are from the cytoplasmic domain of yeast gene a receptor for the Y. is proposed to of by the and a et al., J.L. E. Cell. 1994; Scholar). The domain of contains by a et al., Curr. Opin. Cell. Biol. 1995; 7: Scholar). domain of LR11 to their The in which function as et al., Curr. Opin. Cell. Biol. 1995; 7: Scholar), is found in LR11. the of the protein is to be involved in binding et al., Curr. Opin. Cell. Biol. 1995; 7: Scholar), the homologous in LR11, proposed to be be a for We can to such they might is to complexes and M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Google Scholar); domain of LR11 participate in binding to on the cell of vacuolar protein in yeast and protein in certain cell seem to and proteins, of the domain in and/or highly the complex of LR11 and a in lipoprotein its in tissues with such as brain, liver, and adrenal glands, in which the LDLR is also highly expressed et al., T. Brown M.S. Goldstein J.L. Russell D.W. Science. 1986; 232: Scholar; et al., Lee D. J. Biol. Chem. 1987; Scholar) In the that to with LDLR via its apoE binds to LR11 for the to that a repeat of binding repeat cluster is for in et al. Cell. 1995; Scholar) that in addition to possible ligands, precursor protein and its in In the of a which be the physiological of LR11. The of rabbit and LR11 in the hippocampus, dentate gyrus, and cerebral suggests functional in For instance, receptors, to roles in functions such as and 1993; Scholar), are highly expressed in the et al., H. H. K. E. T. M. T. M. K. M. 1992; LR11 in rabbit as well as in and H. H. J. T. K. J. W. J. and Y. in and the identified LR8B in chicken and (Novak et al., 49Novak S. Hiesberger T. Schneider W.J. Nimpf J. J. Biol. Chem. 1996; 271: 11732-11736Google Scholar) to a new group of LDLR family members with possible The molecular characterization of the complex LR11 new the of the biological of in the expression of homologous functional in different structural The of similarity the proteins from and suggests that the of domains in LR11 been Annu. Rev. Biochem. 1995; Scholar). studies the LR11 in the of cell that of and/or adhesion and to the ligands of this INTRODUCTIONThe discovery of the LDL receptor (LDLR) 1The abbreviations used are: LDLRlow density lipoprotein receptorLR11LDLR relative with 11 binding repeatsLR8(B)LDLR relative with eight binding repeats (B)apoapolipoproteinbpbase pair(s)β-VLDLβ-migrating very low density lipoproteinLRPLDLR related protein/α2-macroglobin receptorEGFepidermal growth factorCHOChinese hamster ovaryPAGEpolyacrylamide gel electrophoresisWHHLWatanabe heritable hyperlipidemicFNIIIfibronectin type III. and its functional and genetic characterization were hallmarks in research on lipoprotein transport pathways and led to the molecular delineation of the common hereditary disease, familial hypercholesterolemia (Brown and Goldstein, 7Brown M.S. Goldstein J.L. Science. 1986; 232: 34-47Google Scholar). In contrast to the clarity of our understanding of LDLR function, the physiological roles of new LDLR homologues, which have been identified in the past decade and form the ever expanding LDLR gene family, are far from being established. Their apparently much more diverse functions are indicated by a wide range of possible ligands, which include spent, biologically inactive and/or unwanted plasma carrier complexes and complex proteins, certain toxins, yolk precursors, as well as circulating plasma lipoproteins (reviewed in Krieger and Herz (35Krieger M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Google Scholar), Schneider and Nimpf (61Schneider W.J. Nimpf J. Curr. Opin. Lipidol. 1993; 4: 205-209Google Scholar), Moestrup (44Moestrup S.K. Biochim. Biophys. Acta. 1994; 1197: 197-213Google Scholar), and Schneider (62Schneider W.J. Curr. Opin. Lipidol. 1995; 6: 92-96Google Scholar)). The bewildering array of ligands they can bind, at least in vitro, is probably due to their highly variable content of different numbers and combinations of common structural elements.To date, these identified common structural modules are (i) the so-called “LDLR ligand binding repeats,” complement-type domains consisting of ~40 residues displaying a triple-disulfide bond-stabilized negatively charged surface; (ii) epidermal growth factor precursor-type repeats, also containing six cysteines each; (iii) modules of ~50 residues each, most often in groups of five, with a consensus tetrapeptide, Tyr-Trp-Thr-Asp (LDLR “YWTD” repeats); and (iv) in the cytoplasmic region, signals for receptor internalization via coated pits, containing the consensus tetrapeptide Asn-Pro-Xaa-Tyr (NPXY) (Chen et al., 11Chen W.-J. Goldstein J.L. Brown M.S. J. Biol. Chem. 1990; 265: 3116-3123Google Scholar).The best characterized binding domain is that of the LDLR, which consists of seven complement-type repeats and recognizes apolipoprotein (apo) B and apoE (Russel et al., 1989). LDLR family members harbor from 1 to 4 clusters with varying numbers of ligand binding repeats. To date, the family includes in addition to the LDLR, the very low density lipoprotein (VLDL) receptor (Takahashi et al., 67Takahashi S. Kawarabayasi Y. Nakai T. Sakai J. Yamamoto T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9252-9256Google Scholar; Bujo et al., 8Bujo H. Hermann M. Kaderli M.O. Jacobsen L. Sugawara S. Nimpf J. Yamamoto T. Schneider W.J. EMBO J. 1994; 13: 5165-5175Google Scholar), Drosophila yolkless (Yl) (Schonbaum et al., 63Schonbaum C.P. Lee S. Mahowald A.P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1485-1489Google Scholar), LDLR related protein/α2-macroglobulin receptor (LRP) (Herz et al. 20Herz J. Hamann U. Rogne S. Myklebost O. Gausepohl H. Stanley K.K. EMBO J. 1988; 7: 4119-4127Google Scholar), the Caenorhabditis elegans LRP-like gene (Yochem and Greenwald, 75Yochem J. Greenwald I. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4572-4576Google Scholar), and gp330/megalin (Saito et al., 58Saito A. Pietromonaco S. Loo A.K.-C. Farquhar M.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9725-9729Google Scholar). Extensive studies on the ligand specificities of these proteins have shown that they likely are multifunctional receptors, cellular uptake of plasma lipoproteins being just one of their tasks. For instance, one of the functionally best documented receptor, the chicken oocytes' eight ligand binding repeat receptor, termed LR8 (Bujo et al., 10Bujo H. Lindstedt K.A. Hermann M. Dalmau L.M. Nimpf J. Schneider W.J. J. Biol. Chem. 1995; 270: 23546-23551Google Scholar), takes up the yolk precursors, riboflavin binding protein (Mac Lachlan et al., 37Mac Lachlan I. Nimpf J. Schneider W.J. J. Biol. Chem. 1994; 269: 24127-24132Google Scholar), α2-macroglobulin (Jacobsen et al., 26Jacobsen L. Hermann M. Vieira P.M. Schneider W.J. Nimpf J. J. Biol. Chem. 1995; 270: 6468-6475Google Scholar), VLDL, and vitellogenin (Bujo et al., 8Bujo H. Hermann M. Kaderli M.O. Jacobsen L. Sugawara S. Nimpf J. Yamamoto T. Schneider W.J. EMBO J. 1994; 13: 5165-5175Google Scholar). Chicken LR8 also recognizes the iron-binding protein, lactoferrin (Hiesberger et al., 21Hiesberger T. Hermann M. Jacobsen L. Novak S. Hodits R.A. Bujo H. Meilinger M. Hüttinger M. Schneider W.J. Nimpf J. J. Biol. Chem. 1995; 270: 18219-18226Google Scholar). Importantly, a mutation in LR8 (ovr−) lends genetic proof to LR8's function as yolk precursor transporter: it causes female sterility (non-laying) and severe hyperlipidemia with associated premature atherosclerosis (Bujo et al., 9Bujo H. Yamamoto T. Hayashi K. Hermann M. Nimpf J. Schneider W.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9905-9909Google Scholar).Without question, the ligand binding repeats are the most characteristic structural modules of the LDLR gene family. However, in a wide variety of species these subdomains have been shuffled into proteins whose functions seem to be unrelated to lipoprotein metabolism. Among these are several proteins of the blood complement system (Haefliger et al. (19Haefliger J.-A. Tschopp J. Nardelli D. Wahli W. Kocher H.-P. Tosi M. Stanley K.K. Biochemistry. 1987; 26: 3551-3556Google Scholar), reviewed in Hobbs et al. (22Hobbs H.H. Russell D.W. Brown M.S. Goldstein J.L. Annu. Rev. Genet. 1990; 24: 133-170Google Scholar)); a basement membrane heparan sulfate proteoglycan, perlecan (Noonan et al., 47Noonan D.M. Fulle A. Valente P. Cai S. Horigan E. Sasaki M. Yamada Y. Hassell J.R. J. Biol. Chem. 1991; 266: 22939-22947Google Scholar; Kallunki and Tryggvason, 28Kallunki P. Tryggvason K. J. Cell Biol. 1992; 116: 559-571Google Scholar); a rat apical early endosomal glycoprotein (Speelman et al., 64Speelman B.A. Allen K. Grounds T.L. Neutra M.R. Kirchhausen T. Wilson J.M. J. Biol. Chem. 1995; 270: 1583-1588Google Scholar); a cortical granule protein in sea urchin (Wessel, 72Wessel G.M. Dev. Biol. 1995; 167: 388-397Google Scholar); a linker chain of earthworm hemoglobin (Suzuki and Riggs, 66Suzuki T. Riggs A.F. J. Biol. Chem. 1993; 268: 13548-13555Google Scholar); a G-protein coupled receptor in the ganglion of Lymnaea (Tensen et al., 70Tensen C.P. van Kesteren E.R. Planta R.J. Cox K.J.A. Burke J.F. van Heerikhuizen H. Vreugdenhil E. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 4816-4820Google Scholar); and a chicken rous sarcoma virus receptor (Bates et al., 4Bates P. Young J.A.T. Varmus H.E. Cell. 1993; 74: 1043-1051Google Scholar). Thus, the complement-type repeats in the LDLR are shared by a number of proteins that participate in diverse biological processes. For instance, the occurrence of complement-type repeats together with EGF precursor homology domain(s) in some extracellular matrix proteins, such as perlecan, suggests that certain family members might be involved in cell growth and cellular attachment.We now have discovered a novel and unusually complex member of the LDLR gene family from rabbit. The predominant domain of the type I membrane protein consists of a cluster of 11 LDLR ligand binding repeats; according to our preferred nomenclature which avoids confusing and/or unproven ligand designations (Bujo et al., 10Bujo H. Lindstedt K.A. Hermann M. Dalmau L.M. Nimpf J. Schneider W.J. J. Biol. Chem. 1995; 270: 23546-23551Google Scholar), the new receptor is termed LR11. It also contains sequences highly homologous to a yeast receptor for vacuolar protein sorting, and to cellular adhesion molecules. Highly expressed in brain, LR11 and a 130-kDa receptor, LR8B (Novak et al., 49Novak S. Hiesberger T. Schneider W.J. Nimpf J. J. Biol. Chem. 1996; 271: 11732-11736Google Scholar) are proposed to be members of a hitherto unknown branch of the LDLR gene family which participate in physiological processes.
Yamazaki et al. (Tue,) studied this question.