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Ligand-binding domains in vitellogenin receptors and other LDL-receptor family members share a common ancestral ordering of cysteine-rich repeats

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Abstract

Insect vitellogenin and yolk protein receptors (VgR/YPR) are newly discovered members of the low-density lipoprotein receptor (LDLR) family, which is characterized by a highly conserved arrangement of repetitive modular elements homologous to functionally unrelated proteins. The insect VgR/YPRs are unique in having two clusters of complement-type cysteine-rich (class A) repeats or modules, with five modules in the first cluster and seven in the second cluster, unlike classical LDLRs which have a single seven-module cluster, vertebrate VgRs and very low density lipoprotein receptors (VLDLR) which have a single eight-module cluster, and LDLR-related proteins (LRPs) and megalins which have four clusters of 2–7, 8, 10, and 11 modules. Alignment of clusters across subfamilies by conventional alignment programs is problematic because of the repetitive nature of the component modules which may have undergone rearrangements, duplications, and deletions during evolution. To circumvent this problem, we “fingerprinted” each class A module in the different clusters by identifying those amino acids that are both relatively conserved and relatively unique within the cluster. Inter-cluster reciprocal comparisons of fingerprints and aligned sequences allowed us to distinguish four cohorts of modules reflecting shared recent ancestry. All but two of the 57 modules examined could be assigned to one of these four cohorts designated A, B, C, and D. Alignment of clusters based on modular cohorts revealed that all clusters are derived from a single primordial cluster of at least seven modules with a consensus arrangement of CDCADBC. All extant clusters examined are consistent with this consensus, though none matches it perfectly. This analysis also revealed that the eight-module clusters in vertebrate VgRs, insect VgR/YPRs, and LRP/ megalins are not directly homologous with one another. Assignment of modules to cohorts permitted us to properly align 32 class A clusters from all four LDLR subfamilies for phylogenetic analysis. The results revealed that smaller one-cluster and two-cluster members of the family did not originate from the breakup of a large two-cluster or four-cluster receptor. Similarly, the LRP/ megalins did not arise from the duplication of a two-cluster insect VgR/YPR-like progenitor. Rather, it appears that the multicluster receptors were independently constructed from the same single-cluster ancestor.

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References

  • Andreasen PA, Sottrup-Jensen L, Kjöller L, Nykjær A, Moestrup SK, Petersen CM, Gliemann J (1994) Receptor-mediated endocytosis of plasminogen activators and activator/inhibitor complexes. FEBS Lett 338:239–245

    Article  PubMed  CAS  Google Scholar 

  • Avise JC (1994) Molecular markers, natural history and evolution. Chapman and Hall, New York, NY

    Google Scholar 

  • Bishop RW (1992) Structure of the hamster low density lipoprotein receptor gene. J Lipid Res 33:549–557

    PubMed  CAS  Google Scholar 

  • Bownes M, Shirras A, Blair M, Collins J, Coulson A (1988) Evidence that insect embryogenesis is regulated by ecdysteroids released from yolk proteins. Proc Natl Acad Sci USA 85:1554–1557

    Article  PubMed  CAS  Google Scholar 

  • Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47

    Article  PubMed  CAS  Google Scholar 

  • Bujo H, Hermann M, Kaderli MO, Jacobsen L, Sugawara S, Nimpf J, Yamamoto T, Schneider WJ (1994) Chicken oocyte growth is mediated by an eight ligand binding repeat member of the LDL receptor family. EMBO J 13:5165–5175

    PubMed  CAS  Google Scholar 

  • Bujo H, Lindstedt KA, Hermann M, Dalmau LM, Nimpf J, Schneider WJ (1995) Chicken oocytes and somatic cells express different splice variants of a multifunctional receptor. J Biol Chem 270: 23546–23551

    Article  PubMed  CAS  Google Scholar 

  • Chen J-S, Sappington TW, Raikhel AS (1997) Extensive sequence conservation among insect, nematode, and vertebrate vitellogenins reveals ancient common ancestry. J Mol Evol 44:440–451

    Article  PubMed  CAS  Google Scholar 

  • Daly NL, Scanlon MJ, Djordjevic JT, Kroon PA, Smith R (1995a) Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. Proc Natl Acad Sci USA 92:6334–6338

    Article  PubMed  CAS  Google Scholar 

  • Daly NL, Djordjevic JT, Kroon PA, Smith R (1995b) Three-dimensional structure of the second cysteine-rich repeat from the human low-density lipoprotein receptor. Biochemistry 34:14474–14481

    Article  PubMed  CAS  Google Scholar 

  • Dhadialla TS, Hays AR, Raikhel AS (1992) Characterization of the solubilized mosquito vitellogenin receptor. Insect Biochem Mol Biol 22:803–816

    Article  CAS  Google Scholar 

  • Ebina S, Matsubara K, Nagayama K, Yamaki M, Gotoh T (1995) Carbohydrate gluing, an architectural mechanism in the supramolecular structure of an annelid giant hemoglobin. Proc Natl Acad Sci USA

  • Esser V, Limbird LE, Brown MS, Goldstein JL, Russell DW (1988) Mutational analysis of the ligand binding domain of the low density lipoprotein receptor. J Biol Chem 263:13282–13290

    PubMed  CAS  Google Scholar 

  • Farquhar MG, Saito A, Kerjaschki D, Orlando RA (1995) The Hey- mann nephritis antigenic complex: megalin (gp33O) and RAP. J Am Soc Nephrol 6:35–47

    PubMed  CAS  Google Scholar 

  • Genetics Computer Group (1994) Wisconsin sequence analysis pack- age program manual, version 8. Genetics Computer Group, Inc., Madison, WI

    Google Scholar 

  • Gliemann J, Nykjasr A, Petersen CM, Jorgensen KE, Nielsen M, Andreasen PA, Christensen El, Lookene A, Olivecrona G, Moestrup SK (1994) The multiligand a2-macroglobulin receptor/low density lipoprotein receptor-related protein (a2MR/LRP): binding and endocytosis of fluid phase and membrane-associated ligands. Ann NY Acad Sci 737:20–38

    Article  PubMed  CAS  Google Scholar 

  • Goldstein JL, Brown MS, Anderson RGW, Russell DW, Schneider WJ (1985) Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol 1:1–39

    Article  PubMed  CAS  Google Scholar 

  • Herz J, Hamann U, Rogne S, Myklebost O, Gausepohl H, Stanley KK (1988) 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 7:4119–127

    PubMed  CAS  Google Scholar 

  • Hiesberger T, Hodits R, Ullrich R, Exner M, Kerjaschki D, Schneider WJ, Nimpf J (1996) Receptor-associated protein and members of the low density lipoprotein receptor family share a common epitope: an extended model for the development of passive Heymann nephritis. J Biol Chem 271:28792–28797

    Article  PubMed  CAS  Google Scholar 

  • Hjälm G, Murray E, Crumley G, Harazim W, Lundgren S, Onyango I, Ek B, Larsson M, Juhlin C, Hellman P, Davis H, åkerstrom G, Rask L, Morse B (1996) Cloning and sequencing of human gp330, a Ca2+-binding receptor with potential intra-cellular signaling properties. Eur J Biochem 239:132–137

    Article  PubMed  Google Scholar 

  • Hobbs HH, Brown MS, Goldstein JL, Russell DW (1986) Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hy-percholesterolemia. J Biol Chem 261:13114–13120

    PubMed  CAS  Google Scholar 

  • Hong CC, Hashimoto C (1995) An unusual mosaic protein with a protease domain, encoded by the nudel gene, is involved in defining embryonic dorsoventral polarity in Drosophila. Cell 82:785–794

    Article  PubMed  CAS  Google Scholar 

  • Jokinen EV, Landschultz KT, Wyne KL, Ho YK, Frykman PK, Hobbs HH (1994) Regulation of the very low density lipoprotein receptor by thyroid hormone in rat skeletal muscle. J Biol Chem 269:26411–26418

    PubMed  CAS  Google Scholar 

  • Kim D-H, Iijima H, Goto K, Sakai J, Ishii H, Kim H-J, Suzuki H, Kondo H, Saeki S, Yamamoto T (1996) Human apolipoprotein E receptor 2: a novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in brain. J Biol Chem 271:8373–8380

    Article  PubMed  CAS  Google Scholar 

  • Koller CN, Dhadialla TS, Raikhel AS (1989) Selective endocytosis of vitellogenin by oocytes of the mosquito, Aedes aegypti: an in vitro study. Insect Biochem 19:693–702

    Article  CAS  Google Scholar 

  • Mehta KD, Chen W-J, Goldstein JL, Brown MS (1991) The low density lipoprotein receptor in Xenopus laevis I. Five domains that resemble the human receptor. J Biol Chem 266:10406–10414

    PubMed  CAS  Google Scholar 

  • Mehta KD, Chang R, Norman J (1996) Chiloscyllium plagiosum low-density lipoprotein receptor: evolutionary conservation of five different functional domains. J Mol Evol 42:264–272

    Article  PubMed  CAS  Google Scholar 

  • Moestrup SK (1994) The α2-macroglobulin receptor and epithelial gly-coprotein-330: two giant receptors mediating endocytosis of multiple ligands. Biochim Biophys Acta 1197:197–213

    PubMed  CAS  Google Scholar 

  • Nimpf J, Schneider WJ (1994) The chicken LDL receptor-related pro-tein/α2-macroglobulin receptor family. Ann NY Acad Sci 737:145–153

    Article  PubMed  CAS  Google Scholar 

  • Nimpf J, Stifani S, Bilous PT, Schneider WJ (1994) The somatic cell-specific low density lipoprotein receptor-related protein of the chicken: close kinship to mammalian low density lipoprotein receptor gene family members. J Biol Chem 269:212–219

    PubMed  CAS  Google Scholar 

  • Okabayashi K, Shoji H, Nakamura T, Hashimoto O, Asashima M, Sugino H (1996) cDNA cloning and expression of the Xenopus laevis vitellogenin receptor. Biochem Biophys Res Commun 224: 406–413

    Article  PubMed  CAS  Google Scholar 

  • Polvio WJ, Dichek DA, Mason J, Anderson WF (1992) Molecular cloning and nucleotide sequence of cDNA encoding a functional murine low density lipoprotein receptor. Somat Cell Genet 18:443–450

    Article  Google Scholar 

  • Rong L, Bates P (1995) Analysis of the subgroup A avian sarcoma and leukosis virus receptor: the 40-residue, cysteine-rich, low-density lipoprotein receptor repeat motif of Tva is sufficient to mediate viral entry. J Virol 69:4847–4853

    PubMed  CAS  Google Scholar 

  • Russell DW, Brown MS, Goldstein JL (1989) Different combinations of cysteine-rich repeats mediate binding of low density lipoprotein receptor to two different proteins. J Biol Chem 264:21682–21688

    PubMed  CAS  Google Scholar 

  • Saito A, Pietromonaco S, Loo AK-C, Farquhar MG (1994) Complete cloning and sequencing of rat gp330/“megalin,” a distinctive member of the low density lipoprotein receptor gene family. Proc Natl Acad Sci USA 91:9725–9729

    Article  PubMed  CAS  Google Scholar 

  • Sakai J, Hoshino A, Takahashi S, Miura Y, Hirofumi I, Hiroyuki S, Kawarabayasi Y, Yamamoto T (1994) Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene. J Biol Chem 269:2173–2182

    PubMed  CAS  Google Scholar 

  • Sappington TW, Hays AR, Raikhel AS (1995) Mosquito vitellogenin receptor: purification, developmental and biochemical characterization. Insect Biochem Mol Biol 25:807–817

    Article  PubMed  CAS  Google Scholar 

  • Sappington TW, Kokoza VA, Cho W-L, Raikhel AS (1996) Molecular characterization of the mosquito vitellogenin receptor reveals unexpected high homology to the Drosophila yolk protein receptor. Proc Natl Acad Sci USA 93:8934–8939

    Article  PubMed  CAS  Google Scholar 

  • Schonbaum CP, Lee S, Mahowald AP (1995) The Drosophila yolkless gene encodes a vitellogenin receptor belonging to the low density lipoprotein receptor superfamily. Proc Natl Acad Sci USA 92: 1485–1489

    Article  PubMed  CAS  Google Scholar 

  • Speelman BA, Allen K, Grounds TL, Neutra MR, Kirchhausen T, Wilson JM (1995) Molecular characterization of an apical early endosomal glycoprotein from developing rat intestinal epithelial cells. J Biol Chem 270:1583–1588

    Article  PubMed  CAS  Google Scholar 

  • Strickland DK, Kounnas MZ, Williams SE, Argraves WS (1994) LDL receptor-related protein (LRP): a multiligand receptor. Fibrinolysis 8 Suppl 1:204–215

    Article  CAS  Google Scholar 

  • Südhof TC, Goldstein JL, Brown MS, Rüssel DW (1985) The LDL receptor gene: a mosaic of exons shared with different proteins. Science 228:815–822

    Article  PubMed  Google Scholar 

  • Suzuki T, Riggs AF (1993) Linker chain LI of earthworm hemoglobin: structure of gene and protein: homology with low density lipoprotein receptor. J Biol Chem 268:13548–13555

    PubMed  CAS  Google Scholar 

  • Swofford DL (1993) PAUP: phylogenetic analysis using parsimony, version 3.1. Computer program distributed by the Illinois Natural History Survey, Champaign, IL

    Google Scholar 

  • Swofford DL, Olsen GJ (1990) Phylogeny reconstruction. In: Hillis DM, Moritz C (eds) Molecular systematics. Sinauer, Sunderland, MA, pp 411–501

    Google Scholar 

  • Takahashi S, Kawarabayasi Y, Nakai T, Sakai J, Yamamoto T (1992) Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor-like protein with distinct ligand specificity. Proc Natl Acad Sci USA 89:9252–9256

    Article  PubMed  CAS  Google Scholar 

  • Tensen CP, Kesteren ER, Planta RJ, Cox K, Burke JF, Keerikhuizen H, Vreugdenhil E (1994) 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 USA 91:4816–4820

    Article  PubMed  CAS  Google Scholar 

  • Ullman CG, Haris PI, Smith KF, Sim RB, Emery VC, Perkins SJ (1995) β-Sheet secondary structure of an LDL receptor domain from complement factor I by consensus structure predictions and spectroscopy. FEBS Lett 371:199–203

    Article  PubMed  CAS  Google Scholar 

  • Wessel GM (1995) A protein of the sea urchin cortical granules is targeted to the fertilization envelope and contains an LDL-receptor-like motif. Dev Biol 167:388–397

    Article  PubMed  CAS  Google Scholar 

  • Willnow TE, Orth K, Herz J (1994) Molecular dissection of ligand binding sites on the low density lipoprotein receptor-related protein. J Biol Chem 269:15827–15832

    PubMed  CAS  Google Scholar 

  • Yamamoto T, Davis CG, Brown MS, Schneider WJ, Casey ML, Goldstein JL, Russell DW (1984) The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell 39:27–38

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto T, Bishop RW, Brown MS, Goldstein JL, Russell DW (1986) Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit. Science 232:1230–1237

    Article  PubMed  CAS  Google Scholar 

  • Yamazaki H, Bujo H, Kusunoki J, Seimiya K, Kanaki T, Morisaki N, Schneider WJ, Saito Y (1996) Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian low density lipoprotein receptor family member. J Biol Chem 271:24761–24768

    Article  PubMed  CAS  Google Scholar 

  • Yochem J, Greenwald I (1993) A gene for a low density lipoprotein receptor-related protein in the nematode Caenorhabditis elegans. Proc Natl Acad Sci USA 90:4572–4576

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Entomology, Programs in Genetics and Cell and Molecular Biology, Michigan State University, S-138 Plant Biology Building, 48824, East Lansing, MI, USA

    Thomas W. Sappington & Alexander S. Raikhel

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  1. Thomas W. Sappington
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  2. Alexander S. Raikhel
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Correspondence to Thomas W. Sappington.

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Sappington, T.W., Raikhel, A.S. Ligand-binding domains in vitellogenin receptors and other LDL-receptor family members share a common ancestral ordering of cysteine-rich repeats. J Mol Evol 46, 476–487 (1998). https://doi.org/10.1007/PL00006328

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