Worm Breeder's Gazette 11(4): 69
These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.
Endocytosis of cholesterol from serum is mediated in vertebrates by the low density lipoprotein receptor present on the surface of cells. Molecular cloning of the gene and biochemical studies of the receptor have revealed a protein composed of several motifs in addition to a membrane spanning domain and a small intercellular domain that mediates clustering into coated pits. The extracellular portion has repeats of two cysteine-rich amino acid sequence motifs. One motif, termed Class A, is repeated in tandem seven times. Acidic amino acids in the repeats bind basic amino acids present in the protein of LDL particles. The other cysteine-rich motif, repeated three times, resembles epidermal growth factor. The second and third EGF-like repeats are separated by a 275 amino acid stretch composed of five 'YWTD' repeats since these amino acids or closely related amino acids appear at a characteristic position in each repeat We have isolated by low-stringency hybridization with probes from lin-12 and glp-1 a gene in C. elegans that encodes a protein with the features of the vertebrate LDL receptor (WBG 11 p.45). The product was expected to be much larger than the vertebrate receptor because the overall structure of the extracellular portion appeared to be repeated four times before a potential membrane spanning domain. The complete DNA sequence of the gene now allows a direct comparison with the LDL receptor as shown here in schematic form along with the mammalian EGF precursor since it also shares features. The C. elegans gene appears to be a molecular homolog of a mammalian gene encoding a large protein (LRP for LDL receptor related protein) which is thought to function as a lipoprotein receptor distinct from the LDL receptor (Helz ct al. EMBO J. 7, 4119 ). As shown in the diagram, the proteins are very similar throughout their lengths. The C terminal most EGF-like repeat in the nematode product is more like EGF than the other repeats and is termed a class B.1 repeat to distinguish it. The mammalian protein has six Class B.1 repeats in tandem just before the membrane spanning domain. The C. elegans and human LRFs contain a sequence in their cytoplasmic domains that in the LDL receptor mediates clustering into coated pits. The features of the nematode LRP suggest that it might function in a general endocytosis of a lipoprotein particle, possibly a particle containing cholesterol, an essential nutrient for nematodes. The structure is also consistent with a vitellogenin receptor for oocytes, and perhaps it participates in this specific process as well as in the more general uptake of cholesterol by other cells. We hope to examine these possibilities. A low-stringency hybridization screen with parts of the C. elegans LRP gene has yielded one other gene encoding a protein with Class A cysteine repeats. Analysis of genomic and cDNA sequences indicates that the protein is not a direct homolog of the LDL receptor or of any reported protein. [See Figure 1]