© 1997 American Heart Association, Inc.
Articles |
A Novel Mosaic Protein Containing LDL Receptor Elements Is Highly Conserved in Humans and Chickens
From the Department of Molecular Genetics, Biocenter and University of Vienna, Austria (S.M., H.B., J.N., W.J.S.); the Second Department of Internal Medicine, Chiba University School of Medicine, Japan (H.Y., H.B., J.K., T.K., K.S., N.M., Y.S.); and the Department of Cell Biology, Kowa Research Institute, Kowa Co Ltd, Tsukuba, Japan (H.Y.).
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Certain receptors belonging to the LDL receptor (LDLR) gene family appear to constitute a newly identified branch whose members are expressed in brain, in addition to other tissues. In support of this concept, we have now discovered the expression and delineated the molecular structures of a representative of this emerging branch from two such diverse species as human and chicken. This membrane receptor, called LR11 and thus far only known to exist in the rabbit, is a complex seven-domain mosaic protein containing, among other structural elements, a cluster of 11 LDLR ligand-binding repeats and a domain with homology to VPS10, a yeast receptor for vacuolar protein sorting. Cytoplasmic signature sequences define the receptor as competent for endocytosis. The most striking properties of LR11s are their (1) high degree of structural conservation (>80% identity among mammals and birds), with 100% identity in the membrane-spanning and cytoplasmic domains of rabbit and human; (2) lack of regulation by cholesterol and estrogen; and (3) expression in brain. The features of LR11 suggest important roles in intercellular and intracellular ligand transport processes, some of which it may share with other brain-specific LDLR family members.
Key Words: cell adhesion • brain • vacuolar protein sorting • gene family
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The large variety of ligands that members of the LDLR gene family can bind is thought to be due at least in part to their highly variable numbers and combinations of common structural elements. These are (1) the so-called "LDLR ligand-binding repeats," complement-type domains consisting of
40 residues displaying a triple disulfide bond–stabilized negatively charged surface; the presence of such repeats is the minimum requirement for a gene product to belong to the LDLR family; (2) epidermal growth factor precursor–type repeats, also containing six cysteines each; (3) modules of 50 residues each, most often in groups of five, with a consensus tetrapeptide, Tyr-Trp-Thr-Asp (LDLR "YWTD" repeats); and (4) in the cytoplasmic region, signals for receptor internalization via coated pits containing the consensus tetrapeptide Asn-Pro-Xaa-Tyr (NPXY).1 The best-characterized binding domain is that of the LDLR, which consists of seven complement-type repeats and recognizes apo B and apo E.2 The other known LDLR family members harbor from one to four clusters with various numbers of ligand-binding repeats. In addition to the LDLR, the family includes the VLDL receptor,3 4 Drosophila yolkless (Yl),5 LRP,6 the C elegans LRP-like gene,7 and gp330/megalin,8 and the three most recent additions, a brain-specific receptor called LR8B in mouse and chicken,9 the so-called apo E receptor 2,10 and the rabbit protein LR11.11
LDLR ligand-binding repeats are also found in proteins whose functions seem to be unrelated to lipoprotein metabolism. Among those known are several proteins of the blood complement system,12 a basement membrane heparan sulfate proteoglycan called perlecan,13 a cortical granule protein in sea urchin,14 a linker chain of earthworm hemoglobin,15 a G protein–coupled receptor in the ganglion of Lymnaea,16 and a chicken Rous sarcoma virus receptor.17 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, differentiation, and attachment processes.
As mentioned above, we recently discovered and molecularly characterized a novel and unusually complex member of the LDLR gene family in the rabbit.11 The predominant domain of this type I membrane protein consists of a cluster of 11 LDLR ligand-binding repeats; according to our preferred nomenclature,18 the new receptor is called LR11. As described here, this unusual protein is not only present but also very similar in such diverse species as rabbits, humans, and our experimental model system, the chicken. The high level of expression of LR11 in brain of several species supports our notion that LR1111 and LR8B9 are members of a hitherto unknown branch of the LDLR gene family that may participate in brain-specific physiological processes.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Cloning Strategy
Sources and housing conditions of experimental animals were as previously described.19 For cloning of LR11s from chicken and human, we used brain cDNA libraries from the respective species (Clontech). The human cDNA library was first screened with JH-1, a cDNA fragment comprising the ligand-binding domain of rabbit LR11.11 Approximately 8x105 recombinant phages were screened by hybridization with the 32P-labeled probe (Megaprime DNA labeling kit, Amersham) in 5x SSC, 5x Denhardt's solution, 1% SDS, 100 µg/mL salmon sperm DNA, and 30% formamide at 42°C for 20 hours.20 The filters were washed in 0.3x SSC, 0.1% SDS at 50°C, and positive clones were subcloned into pBluescript II SK (Stratagene) and sequenced on both sides by use of Sequenase (US Biochemical). One of them, HB 201 (5833 bp), encoded a new sequence homologous to the binding regions of LDL receptor family members. PCR-amplified cDNA corresponding to regions at and beyond both ends of HB 201 were used for subsequent screening rounds; the full-length cDNA was obtained from clones HB 201 (containing the 3'-end) and HB 401 (containing the 5'-end). A similar cloning strategy was applied toward obtaining the chicken LR11 cDNA presented here; the rabbit LR11 clone JH-1,11 encoding the LDLR ligand-binding domains, was used as a screening probe. Nucleotide sequences were analyzed by the DNASIS (Hitachi) and GeneWorks (IntelliGenetics Inc) computer programs. Homology searches were performed with GeneBank R88.0 or SWISS-PROT R31.0. Chromosome assignment of human LR11 was achieved by the use of HB 201 in fluorescence in situ hybridization experiments exactly as previously described.21
Northern Blot Analysis, RT-PCR, and Cell Culture Experiments
Total RNA was extracted from the indicated chicken tissues and cells, and poly(A)+-RNA was isolated as described previously.4 For analysis of human transcripts, we used the human multiple tissue Northern blots, catalogue Nos. 7750-1, 7755-1, and 7760-1 (Clontech). For Northern blot analysis of chicken LR11, poly(A)+-RNA prepared from the indicated tissues and cultured cells was denatured with glyoxal-dimethylsulfoxide, separated by electrophoresis on a 0.8% agarose gel, and blotted onto Hybond-N+ membrane (Amersham) by standard methods.20 For analysis of human transcripts, the above-described multiple-tissue Northern blot membranes (Clontech) were probed with HB 201 and HB 104 (corresponding to the downstream half of human LR11 cDNA). Chicken transcripts were probed with pC3-10, corresponding to nucleotides 2355 through 2772 (specifying part of domain III) and with a DNA fragment encoding part of domain I. Hybridizations were at 42°C in 50% formamide, 5x SSC, 5x Denhardt's solution, 0.1% SDS, 50 mmol/L sodium phosphate (pH 7.0), 100 µg/mL salmon sperm DNA, and 32P-labeled probe. Washing was performed in 0.1x SSC, 0.1% SDS at 50°C. Filters were exposed to Reflection autoradiography film (NEN Research Products) with intensifying screens. RT-PCR specific for chicken LR11 was performed with primers corresponding to nt 2895 through 2916 (sense) and 3534 through 3558 (antisense), and for apo-VLDL-II the primers corresponded to nt 74 through 98 (sense) and 304 through 328 (antisense), respectively.
LMH/2A cells, a chicken hepatocellular carcinoma cell line stably transfected with the chicken estrogen receptor,22 were a kind gift of Dr D.L. Williams. They were cultured as described previously.22 For stimulation of apo-VLDL-II expression, the serum-free medium contained 50 nmol/L moxestrol (DuPont/NEN), a synthetic analogue of 17ß-hydroxyestradiol for the last 24 hours before the cells were harvested.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Upon isolation of cDNAs by homology cloning, we obtained the complete sequence of the human and
72% of the sequence of the chicken homologues of a previously identified 2213-residue rabbit protein called LR11.11 (The nucleotide sequences identified in this study have been deposited in GenBank/EMBL:YO 8109 chicken LR11 and YO 8110 human LR11.)
Fig 1
shows a primary structure comparison of the human and avian LR11 proteins as deduced from their cDNA sequences. Human LR11 cDNA contains an open reading frame of 6642 bp (encoding 2214 amino acids) following an 80-bp 5'-untranslated region (unpublished data, 1996); the cloned homologous partial chicken cDNA codes for 1592 amino acid residues. Despite their considerable size and evolutionary distance, the proteins possess 94% (human versus rabbit11 ) and 84% (human versus chicken) identical residues; furthermore, of the 14 potential N-linked glycosylation sites so far identified in the avian protein, 13 are present in human LR11. These and previous data11 clearly indicate that we now have obtained LR11 cDNAs from three species altogether. In the following, we describe our results from both the human and avian LR11s.
|
The 5'-region of the human cDNA specifies a stretch of hydrophobic amino acid residues (Figs 1
and 2) with a consensus signal sequence cleavage site 28 residues downstream.23 A second hydrophobic region, residues 2136 to 2160, represents a putative transmembrane domain (Figs 1 and 2, and see below). A TGA stop codon is followed by 118 bp of 3' untranslated region. The calculated molecular weight of the mature human protein is 245 355 (rabbit LR11, 244 67811 ). As originally revealed by analysis of rabbit LR11,11 LR11s are made up of seven distinct domains (Fig 2). Domain I comprises the N-terminal 350 amino acids; domain II is related to a yeast receptor for vacuolar protein sorting; domain III consists of five tandem LDLR "YWTD" repeats and domain IV of 11 LDLR ligand-binding repeats; domain V comprises six motifs related to the fibronectin-type (FN) III repeat; domain VI is the single putative membrane-spanning region; and domain VII, at the C-terminus, constitutes 50 amino acids predicted to be a cytoplasmatic region with an internalization signal. The partial chicken cDNA revealed a 4776-bp coding sequence missing 280 bp at the N-terminal region and information on the C-terminal 24% of the protein (Figs 1 and 2). However, the delineated primary sequence, which encompasses domains I to V in exactly the same order as found in rabbit and human LR11s (Fig 2), clearly identifies the chicken protein as the first avian LR11.
|
Domain I is, to the best of our knowledge, the only region of LR11 without significant similarities to other proteins yet highly conserved in the regions known from all three LR11s (>80% identical residues). In human and rabbit LR11s, there is an Arg-Gly-Asp (RGD) tripeptide, normally involved in cell binding of a number of extracellular matrix glycoproteins by interaction with integrins (reviewed, eg, in Reference 2424 ), at amino acid residues 63 through 65; the 75% of cloned domain I of chicken LR11 does not cover these residues.
The second domains (390 residues) show high homology to a yeast gene, VPS10.11 25 VPS10, the sorting receptor for soluble vacuolar carboxypeptidase Y,26 is a type I transmembrane protein with a large luminal domain containing two homologous repeats of 650 amino acids each. The identities between parts of the two yeast receptor repeats and the single repeats found in the human and chicken LR11s range from 19% to 29%; notably, all 12 cysteines of the LR11 regions are conserved in the corresponding yeast protein domain.
Following the VPS10-like domains, the next 250 residues contain five repeats of 50 residues each with a consensus tetrapeptide, Y/FWXD (asterisks below Y/F in Fig 1). This region, in all three species and in rabbit and human LR11s, the membrane-spanning and putative intracellular domains, is the most highly conserved feature of LR11. In the LDLR family members characterized to date, such "YWTD" repeats, also usually five, are flanked on both sides by typical EGF precursor motifs containing 6 cysteines each. In the LR11s, they are replaced by a single subdomain with 8 cysteines, which we have assigned to the amino-terminus of domain IV (Reference 1111 and Fig 2).
Domain IV, from which the designation for this novel group of proteins is derived, is composed of 11 tandemly arranged 6-cysteine repeats found in the LDLR ligand-binding domain, preceded by the above-described 8-cysteine subdomain. All 66 cysteines in the 11 ligand-binding repeats as well as the typical Asp-Xaa-Ser-Asp-Glu motifs at their carboxy-terminal region, are absolutely conserved in LR11s and arranged exactly as in other LDLR family members.
Particularly interesting from an evolutionary point of view is the structure of a genomic region corresponding to the ligand-binding repeat domain in chicken LR11. In a preliminary screening round of a chicken genomic library, we isolated and characterized two clones corresponding to LR11 (Fig 3). Sequence analysis revealed that these clones contained DNA coding for ligand-binding repeats 1 and 4 to 9, respectively, of chicken LR11. By sequence alignment with the cDNA clones, we identified introns (gt...ag) following the exon encoding repeat 1 and situated between individual exons coding for repeats 4, 5, 6, 7, 8, and 9, respectively. The gene structure of this region is thus highly reminiscent of that of the new other known (partial) genes specifying LDLR family members, characterized by short exons encoding single or small groups of ligand-binding repeats.7 27 28 29
|
Domain V, which follows immediately after domain IV, contains 586 residues (human LR11) and is composed of six putative FN III repeats (Figs 1 and 2). The characteristic highly conserved tryptophan, tyrosine, and leucine residues, as well as numerous less well conserved amino acids,30 are present in the large majority of the repeats in human and rabbit LR11.
Domain VI, the putative membrane-spanning region (25 mostly hydrophobic residues) is followed by the carboxy-terminal domain VII, presumed to constitute the cytoplasmic region (Figs 1 and 2). Amazingly, domains VI and VII (79 residues) of rabbit and human LR11 are completely identical. In the short cytoplasmic tail, the sequence Phe-Ala-Asn-Ser-His-Tyr (FANSHY, residues 2172 to 2177 of human LR11) is similar to the internalization signal of coated pit receptors (References 11 and 3131 , and see "Discussion"); there are also positively and negatively charged residues near the transmembrane and the C-terminus, respectively, equivalent to those in the similarly short cytoplasmic domains in LDLRs and VLDLRs.
The human LR11 gene locus was mapped to chromosome 11q 23.3-24 by fluorescence in situ hybridization (unpublished data, 1996), and tissue distribution of LR11 transcripts in humans and chicken were determined by Northern blot analysis (Fig 4). In humans (Fig 4A), a transcript of 12 kb was abundant in brain, liver, kidney, and pancreas, with detectable levels in placenta, lung, and heart. The origin of an additional smaller transcript (8 kb) was not determined. The distribution of LR11 in human brain was studied in greater detail (Fig 4B). The most abundant expression of LR11 in brain was detected in the cerebellum, the cerebral cortex, and the occipital pole; expression in the putamen and thalamus was low. When other partial human LR11 cDNA clones were used as probes, we obtained identical results (unpublished data, 1996).
|
Expression of LR11 in chicken was largely similar to that in rabbit (Fig 4C), with the exception of the liver, in which only the rabbit showed clearly detectable transcripts11 ; subsequent hybridization with a ß-actin probe confirmed integrity of the poly(A)+-RNA from all tissues (not shown). LR11 was expressed in the brain of all three species; in humans, brain was the predominant site of expression. As in rabbit testis,11 an additional smaller avian transcript showed cross-hybridization; the nature of this LDLR-related transcript is under investigation.
A hallmark property of the LDLR is its tight regulation by sterols,32 but LR11 transcript levels in the livers of rabbit11 and chicken (eg, LR11 levels are normal in the mutant hypercholesterolemic chicken strain "restricted ovulator,"33 not shown) are refractory to changes in cholesterol content. The availability of the estrogen-responsive chicken hepatic cell line LMH/2A allowed us to study an important regulatory aspect of lipoprotein metabolism in the chicken, ie, the effect of estrogen on gene expression. As shown in Fig 5 for control purposes, estrogen dramatically induces transcription of the avian apolipoprotein, apo-VLDL-II in LMH/2A cells, in agreement with previous reports.22 However, LR11 expression is not changed by the addition of the hormone to the culture medium. Thus, both estrogen status and changes in cholesterol levels lack regulatory effects on LR11.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The high degree of homology between the LDLR gene family members has, in general, been shown to correlate with important biological functions of the proteins.34 35 One exception may be the so-called VLDL receptors, since their functions in mammals have not yet become evident.36 However, in the chicken, a mutation in the corresponding gene rendering the receptor unfunctional causes female sterility and atherosclerosis,33 a result that encouraged us to search for an LR11 homologue in this species. Our present demonstration that LR11 is not restricted to the rabbit but is also expressed and extremely well conserved in human and chicken again raises the possibility that this novel protein fulfills significant biological functions. LR11 is a striking mosaic protein containing several structural elements so far not found in LDLR gene family members, and these may confer unique specificity in terms of molecular interactions with other proteins.
The elements that place LR11 in the LDLR gene family, domains III and IV, themselves display three unusual features, all of which are also present in the human and avian proteins. First, they are separated by a hitherto unknown short domain containing eight cysteine residues, rather than by six-cysteine "EGF precursor type B" repeats,6 which are typical for LDLR family members described to date.11 Second, groups of five YWTD repeats have been found thus far, either downstream or downstream and upstream from the ligand-binding repeat cluster. The presence of five YWTD repeats only at the amino-terminal side of the LR11 binding repeat cluster suggests that there is substantial domain shuffling and that multirepeat modules are conserved because they function as such. Of course, a modifying effect of one domain on the function of neighboring and/or distant domains cannot be excluded. Third, LRP,6 the C elegans putative LRP-like gene product,7 and gp330/megalin8 are the only other proteins that contain clusters of 11 complement-type repeats. In the clusters of these receptors, certain repeats are separated from each other by amino acid stretches called "linker regions."27 LR11s appear to lack a typical linker region; however, a few extra residues preceding repeats 9 and 10, respectively, can be identified. Domain V consists of 6 FN III modules originally defined as 90-residue units repeated 15 times in fibronectin.37 The presence of these repeats in cell adhesion molecules and receptors for cell growth and attachment (see Reference 1111 ) further suggests a potential role of LR11 in cell-cell interaction.
To the best of our knowledge, the amino-terminal domain I of LR11 lacks homologous sequences in current databases, yet it is highly conserved between rabbit,11 human, and chicken. It is notable that rabbit and human LR11 have an Arg-Gly-Asp (RGD) tripeptide in this domain (Fig 1), because this tripeptide is also found in L1 and homologues.24 Future studies will attempt to identify additional vertebrate genes that contain LR11 domain I–like sequences. The conservation of the cytoplasmic domains of rabbit and human LR11 is the highest observed to date for any group of LDLR family members. The signature sequence, Phe-Ala-Asn-Ser-His-Tyr (FANSHY) is highly reminiscent of the sequence FDNPXY, which is the common internalization sequence of LDLR gene family members.1 Other features that strongly suggest that LR11s are endocytosis-competent receptors have been discussed previously.11
Domain II will be the focus of our future studies in vertebrates, because thus far such a domain has been identified only in yeast. The luminal domain of VPS10 contains two imperfectly repeated sequences, each followed by a cysteine-rich motif38 ; LR11 shows striking similarities to both VPS10 repeats, including their cysteine-rich regions. The sequence Phe-Tyr-Val-Phe in VPS10, which may function as a Golgi retention/ retrieval signal,38 is not found in LR11. Because the luminal region of the VPS10 protein is suggested to be involved in CPY binding,38 the homologous region in LR11, proposed to be extracellular, may be a site for ligand-receptor interaction(s).11 Vacuolar protein sorting in yeast and lysosomal protein sorting in certain mammalian cell types seem to share similar mechanisms and proteins, yet any involvement of the VPS10 domain in the intracellular and/or vesicle-mediated routing of LR11 must remain highly speculative.
Although the complex structure of LR11 and sterol insensitivity suggest a function(s) other than in lipoprotein metabolism, its abundance in tissues with active cholesterol metabolism, such as brain, liver, and adrenal glands, in which the LDLR is also highly expressed39 requires attention. Recently, Kounnas et al40 reported that LRP binds, in addition to many other possible ligands, ß-amyloid precursor protein and mediates its degradation in vitro. In the absence of a transgenic animal model, we cannot determine which ligand(s) may be the true physiological partner(s) of LR11. The localization in similar brain regions41 of human LR11 and glutamate receptors, thought to play key roles in active brain functions such as learning,42 suggests the functional significance of LR11 in active brain metabolism.
Thus, LR11 in human, chicken, and rabbit11 ; the recently identified LR8B in chicken and mouse9 ; and the so-called apo E receptor 210 appear to define a new group of LDLR family members with possible brain-specific functions. The molecular characterization of the complex LR11 molecules opens new avenues toward the investigation of the biological significance of apparent redundancy in the expression of homologous functional units in different structural context.
Note added in proof. The degree of homology (percent identity) between domain III of the LR11s of chicken and humans is stated to be 98% in Fig 2. The correct value is 78%, and thus this domain is not the best-conserved region of human and chicken LR11. Consequently, the overall identity between LR11s of humans and chickens is 80% and not 84% as currently stated.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
These studies were supported by grants from the Japanese Ministry of Education, Science, and Culture to Dr Saito and from the Austrian Science Foundation to Dr Schneider (F-0608) and Dr Nimpf (F-0606). We thank Drs H. Tani and M. Nakamura (Kowa Co, Ltd) for support and advice during cDNA cloning.
|
Footnotes |
|---|
Reprint requests to Hideaki Bujo, Second Department of Internal Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260, Japan.
Drs Mörwald and Yamazaki contributed equally to the study.
Received August 2, 1996; accepted September 24, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Chen WJ, Goldstein JL, Brown MS. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J Biol Chem. 1990; 265:3116-3123.
2.
Russell DW, Brown MS, Goldstein JL. Different combinations of cysteine-rich repeats mediate binding of low density lipoprotein receptor to two different proteins. J Biol Chem. 1989;264:21682-21688.
3.
Takahashi S, Kawarabayasi Y, Nakai T, Sakai J, Yamamoto T. Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor-like protein with distinct ligand specificity. Proc Natl Acad Sci U S A. 1992;89:9252-9256.
4. Bujo H, Hermann M, Kaderli MO, Jacobsen L, Sugawara S, Nimpf J, Yamamoto T, Schneider WJ. Chicken oocyte growth is mediated by an eight ligand binding repeat member of the LDL receptor family. EMBO J. 1994;13:5165-5175.[Medline] [Order article via Infotrieve]
5.
Schonbaum CP, Lee S, Mahowald AP. The Drosophila yolkless gene encodes a vitellogenin receptor belonging to the low density lipoprotein receptor superfamily. Proc Natl Acad Sci U S A. 1995;92:1485-1489.
6. Herz J, Hamann U, Rogne S, Myklebost O, Gausepohl H, Stanley KK. Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. EMBO J. 1988;7: 4119-4127.
7. Yochem J, Greenwald I. A gene for an LDL receptor-related protein (LRP) in the nematode C. elegans. Proc Natl Acad Sci U S A. 1993; 90:4572-4576.
8.
Saito A, Pietromonaco S, Loo AK-C, Farquhar MG. Complete cloning and sequencing of rat gp330/`megalin,' a distinct member of the low density lipoprotein receptor gene family. Proc Natl Acad Sci U S A. 1994;91:9725-9729.
9.
Novak S, Hiesberger T, Schneider WJ, Nimpf J. A new low density lipoprotein receptor homologue with 8 ligand binding repeats in brain of chicken and mouse. J Biol Chem. 1996;271:11732-11736.
10.
Kim D-H, Iijima H, Goto K, Sakai J, Ishii H, Kim H-J, Suzuki H, Kondo H, Saeki S, Yamamoto T. Human apolipoprotein E receptor 2: a novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in brain. J Biol Chem. 1996;271:1-8.
11.
Yamazaki H, Bujo H, Kusunoki J, Kouichi S, Kanaki T, Morisaki N, Schneider WJ, Saito Y. Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian LDL receptor family member. J Biol Chem. 1996;271:24761-24768.
12. Haeflinger J-A, Tschopp J, Nardelli D, Wahli W, Kocher HP, Tosi M, Stanley KK. Structural homology of human complement component C8 gamma and plasma protein HC: identity of the cysteine bond pattern. Biochemistry. 1987;26:3551-3556.[Medline] [Order article via Infotrieve]
13. Noonan DM, Fulle A, Valente P, Cai S, Horigan E, Sasaki M, Yamada Y, Hassel JR. The complete sequence of perlecan, a basement membrane heparan sulfate proteoglycan, reveals extensive similarity with laminin A chain, low density lipoprotein-receptor, and the neural cell adhesion molecule. J Biol Chem. 1991;266: 22939-22947.
14. Wessel GM. A protein of the sea urchin cortical granules is targeted to the fertilization envelope and contains an LDL-receptor-like motif. Dev Biol. 1995;167:388-397.[Medline] [Order article via Infotrieve]
15.
Suzuki T, Riggs AF. Linker chain L1 of earthworm hemoglobin: structure of gene and protein: homology with low density lipoprotein receptor. J Biol Chem. 1993;268:13548-13555.
16. Tensen CP, van Kesteren ER, Planta RJ, Cox KJA, Burke JF, van Heerikhuizen H, Vreugdenhil E. A G-protein-coupled receptor with low density lipoprotein-binding motifs suggests a role for lipoproteins in G-linked signal transduction. Proc Natl Acad Sci U S A. 1994; 91:4816-4820.
17. Bates P, Young JAT, Varmus HE. A receptor for subgroup A Rous sarcoma virus is related to the low density lipoprotein receptor. Cell. 1993;74:1043-1051.[Medline] [Order article via Infotrieve]
18.
Bujo H, Lindstedt KA, Hermann M, Dalmau LM, Nimpf J, Schneider WJ. Chicken oocytes and somatic cells express different splice variants of a multifunctional receptor. J Biol Chem. 1995;270:23546-23551.
19.
Jacobsen L, Hermann M, Vieira PM, Schneider WJ, Nimpf J. The chicken oocyte receptor for lipoprotein deposition recognizes 
2-macroglobulin. J Biol Chem. 1995;270:6468-6475.
20. Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual. Plainview, NY: Cold Spring Harbor Laboratory Press; 1989.
21. Nakagawara K, Mori M, Takasawa S, Nata K, Takamura T, Berlova A, Tohgo A, Karasawa T, Yonekura H, Takeuchi T, Okamoto H. Assignment of CD38, the gene encoding human leukocyte antigen CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase), to chromosome 4p15. Cytogenet Cell Genet. 1995;69:38-39.[Medline] [Order article via Infotrieve]
22.
Sensel MG, Binder R, Lazier CB, Williams DL. Reactivation of apolipoprotein II gene transcription by cyclohexamide reveals two steps in the deactivation of estrogen receptor-mediated transcription. Mol Cell Biol. 1994;14:1733-1742.
23. von Heijne G. Patterns of amino acids near signal-sequence cleavage sites. Eur J Biochem. 1983;133:17-21.[Medline] [Order article via Infotrieve]
24.
Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins. Science. 1987;238:491-497.
25.
Robinson JS, Klionsky DJ, Banta LM, Emr SD. Protein sorting in Saccharomyces cerevisiae: isolation of mutants defective in the delivery and processing of multiple vacuolar hydrolases. Mol Cell Biol. 1988;8:4936-4948.
26. Marcusson EG, Horazdovsky BF, Cereghino JL, Gharakhanian E, Emr SD. The sorting receptor for yeast vacuolar carboxypeptidase Y is encoded by the VPS10 gene. Cell. 1994;77:579-586.[Medline] [Order article via Infotrieve]
27.
Südhof TC, Goldstein JL, Brown MS, Russell DW. Cassette of eight exons shared by genes for LDL receptor and EGF precursor. Science. 1985;228:815-822.
28. Van Leuven F, Stas L, Hiliker C, Lorent K, Umans L, Serneels L, Overbergh L, Torrekens S, Moechars D, De Strooper B, Van den Berghe H. Structure of the gene coding for the human alpha-2-macroglobulin receptor/lipoprotein receptor related protein. Genomics. 1995;24:78-89.
29.
Sakai J, Hoshino A, Takahashi S, Miura Y, Ishii H, Suzuki H, Kawarabayasi Y, Yamamoto T. Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene. J Biol Chem. 1994;269:2173-2182.
30. Patthy L. Homology of a domain of the growth hormone/prolactin receptor family with type III modules of fibronectin. Cell. 1990;61:13-14.[Medline] [Order article via Infotrieve]
31.
Naim HY, Roth MG. Characteristics of the internalization signal in the Y543 influenza virus hemagglutinin suggest a model for recognition of internalization signals containing tyrosine. J Biol Chem. 1994;269:3928-3933.
32.
Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34-47.
33.
Bujo H, Yamamoto T, Hayashi K, Hermann M, Nimpf J, Schneider WJ. Mutant oocytic low density lipoprotein receptor gene family member causes atherosclerosis and female sterility. Proc Natl Acad Sci U S A. 1995;92:9905-9909.
34. Herz J, Clouthier DE, Hammer RE. LDL receptor-related-protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell. 1992;71:411-421.[Medline] [Order article via Infotrieve]
35.
Willnow TE, Hilpert J, Armstrong SA, Rohlmann A, Hammer RE, Burns DK, Herz J. Defective forebrain development in mice lacking gp330/megalin. Proc Natl Acad Sci U S A. 1996;93:8460-8464.
36.
Frykman PK, Brown MS, Yamamoto T, Goldstein JL, Herz J. Normal plasma lipoproteins and fertility in gene-targeted mice homozygous for a disruption in the gene encoding very low density lipoprotein receptor. Proc Natl Acad Sci U S A. 1995;92:8453-8457.
37. Kornblihtt AR, Umezawa K, Vibe-Pedersen K, Baralle FE. Primary structure of human fibronectin: differential splicing may generate at least 10 polypeptides from a single gene. EMBO J. 1985;4:1755-1759.[Medline] [Order article via Infotrieve]
38. Horazdovsky BF, DeWald DB, Emr SD. Protein transport to the yeast vacuole. Curr Opin Cell Biol. 1995;7:544-551.[Medline] [Order article via Infotrieve]
39.
Yamamoto T, Bishop RW, Brown MS, Goldstein JL, Russell DW. Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit. Science. 1986;232:1230-1237.
40. Kounnas MZ, Moir RD, Rebeck GW, Bush AI, Argraves WS, Tanzi RE, Hyman BT, Strickland DK. LDL receptor-related protein, a multifunctional apoE receptor, binds secreted ß-amyloid precursor protein and mediates degradation. Cell. 1995;82:331-340.[Medline] [Order article via Infotrieve]
41. Meguro H, Mori H, Araki K, Kushiya E, Kutsuwada T, Yamazaki M, Kumanishi T, Arakawa M, Sakimura K, Mishina M. Functional characterization of a heteromeric NMDA receptor channel expressed from cloned cDNAs. Nature. 1992;357:70-74.[Medline] [Order article via Infotrieve]
42. Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31-39.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. Matsuo, H. Ebinuma, I. Fukamachi, M. Jiang, H. Bujo, and Y. Saito Development of an Immunoassay for the Quantification of Soluble LR11, a Circulating Marker of Atherosclerosis Clin. Chem., October 1, 2009; 55(10): 1801 - 1808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rohe, A.-S. Carlo, H. Breyhan, A. Sporbert, D. Militz, V. Schmidt, C. Wozny, A. Harmeier, B. Erdmann, K. R. Bales, et al. Sortilin-related Receptor with A-type Repeats (SORLA) Affects the Amyloid Precursor Protein-dependent Stimulation of ERK Signaling and Adult Neurogenesis J. Biol. Chem., May 23, 2008; 283(21): 14826 - 14834. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Iwaki, A. Hosomi, S. Tokudomi, Y. Kusunoki, Y. Fujita, Y. Giga-Hama, N. Tanaka, and K. Takegawa Vacuolar protein sorting receptor in Schizosaccharomyces pombe. Microbiology, May 1, 2006; 152(Pt 5): 1523 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhu, H. Bujo, H. Yamazaki, K. Ohwaki, M. Jiang, S. Hirayama, T. Kanaki, M. Shibasaki, K. Takahashi, W. J. Schneider, et al. LR11, an LDL Receptor Gene Family Member, Is a Novel Regulator of Smooth Muscle Cell Migration Circ. Res., April 2, 2004; 94(6): 752 - 758. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Taira, H. Bujo, S. Hirayama, H. Yamazaki, T. Kanaki, K. Takahashi, I. Ishii, T. Miida, W. J. Schneider, and Y. Saito LR11, a Mosaic LDL Receptor Family Member, Mediates the Uptake of ApoE-Rich Lipoproteins In Vitro Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1501 - 1506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. I. Posse de Chaves, D. E. Vance, R. B. Campenot, R. S. Kiss, and J. E. Vance Uptake of Lipoproteins for Axonal Growth of Sympathetic Neurons J. Biol. Chem., June 23, 2000; 275(26): 19883 - 19890. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W Hampe, I. Riedel, J Lintzel, C. Bader, I Franke, and H. Schaller Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator J. Cell Sci., January 12, 2000; 113(24): 4475 - 4485. [Abstract] [PDF]
|
|
|
|
|
|
T. Kanaki, H. Bujo, S. Hirayama, I. Ishii, N. Morisaki, W. J. Schneider, and Y. Saito Expression of LR11, a Mosaic LDL Receptor Family Member, Is Markedly Increased in Atherosclerotic Lesions Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2687 - 2695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W Hampe, J Urny, I Franke, S. Hoffmeister-Ullerich, D Herrmann, C. Petersen, J Lohmann, and H. Schaller A head-activator binding protein is present in hydra in a soluble and a membrane-anchored form Development, January 9, 1999; 126(18): 4077 - 4086. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Kuhlbrodt, B. Herbarth, E. Sock, I. Hermans-Borgmeyer, and M. Wegner Sox10, a Novel Transcriptional Modulator in Glial Cells J. Neurosci., January 1, 1998; 18(1): 237 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Lindstedt, M. G. Mahon, R. Foisner, M. Hermann, J. Nimpf, and W. J. Schneider Receptor-associated Protein in an Oviparous Species Is Correlated with the Expression of a Receptor Variant J. Biol. Chem., November 28, 1997; 272(48): 30221 - 30227. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Jacobsen, P. Madsen, C. Jacobsen, M. S. Nielsen, J. Gliemann, and C. M. Petersen Activation and Functional Characterization of the Mosaic Receptor SorLA/LR11 J. Biol. Chem., June 15, 2001; 276(25): 22788 - 22796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhu, H. Bujo, H. Yamazaki, S. Hirayama, T. Kanaki, K. Takahashi, M. Shibasaki, W. J. Schneider, and Y. Saito Enhanced Expression of the LDL Receptor Family Member LR11 Increases Migration of Smooth Muscle Cells In Vitro Circulation, April 16, 2002; 105(15): 1830 - 1836. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||