Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2008) Nucleic Acids Res , doi:10.1093/nar/gkn808

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LY Low-density lipoprotein-receptor YWTD domain

There are 8212 LY domains in 838 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a LY domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with LY domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Takifugu rubripes

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Saito A, Pietromonaco S, Loo AK, Farquhar MG
  • Complete cloning and sequencing of rat gp330/"megalin," a distinctive member of the low density lipoprotein receptor gene family.
  • Proc Natl Acad Sci U S A. 1994; 91: 9725-9
  • Display abstract

  • We completed the cDNA cloning and sequencing of gp330, the major kidney glomerular antigen for rat Heymann nephritis. The deduced 4660-aa sequence, expected to constitute a mature protein of M(r) 516,715, consists of a probable N-terminal signal peptide sequence (25 aa), an extracellular region (4400 aa), a single transmembrane domain (22 aa), and a C-terminal cytoplasmic tail (213 aa). The extracellular region contains three types of cysteine-rich repeats characteristic of the low density lipoprotein receptor (LDLR) gene family--36 LDLR ligand-binding repeats forming four clusters of putative ligand-binding domains, 16 growth factor repeats separated by 8 YWTD spacer regions, and 1 C-terminal epidermal growth factor repeat. The cytoplasmic tail contains two copies of the (FX)NPXY motif, which represents a signal for coated pitmediated internalization and an additional similar motif. The overall structure of gp330 is similar to that of the LDLR-related protein (LRP)/alpha 2-macroglobulin receptor and shows even greater similarity to the Caenorhabditis elegans protein, reported as a homologue of LRP. However, gp330 differs from these proteins in (i) the cysteine-rich repeat arrangements found in the extreme extracellular N- and C-terminal regions, (ii) the distribution pattern of cysteine residues in the YWTD spacer regions, (iii) the location of the RX(K/R)R consensus recognition sequence of furin, a precursor processing endoprotease, and (iv) the length and structure of the cytoplasmic tail. We suggest the name megalin (from Greek mega) for gp330, the largest plasma membrane protein identified so far in vertebrates. The cloned cDNA will be useful for studies on the physiological functions of gp330/megalin and for determining its role in Heymann nephritis.

  • Yamamoto T et al.
  • The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA.
  • Cell. 1984; 39: 27-38
  • Display abstract

  • The nucleotide sequence of a cloned 5.3 kilobase cDNA for the human low density lipoprotein receptor revealed five domains in the 839 amino acid protein: 322 NH2-terminal amino acids, extremely rich in disulfide-bonded cysteine residues (15%) and including an 8-fold repeat of 40 residues that may contain the LDL binding site; 350 residues homologous to the precursor of mouse epidermal growth factor; a region immediately outside the plasma membrane, rich in serine and threonine and the site of O-linked glycosylation; 22 hydrophobic amino acids, spanning the plasma membrane; and 50 COOH-terminal amino acids, projecting into the cytoplasm. The mRNA for the receptor contains a 3' untranslated region of 2.5 kilobases that includes multiple copies of the Alu family of repetitive DNAs. Transfection of simian COS cells with the human LDL receptor cDNA linked to the SV40 early promoter resulted in expression of functional cell surface receptors.

• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the LY domain.

  Protein	Disease
  Low-density lipoprotein receptor precursor (SRS)(SMART)	OMIM:143890: Hypercholesterolemia, familial

• Metabolism (metabolic pathways involving proteins which contain this domain)

• Click the image to view the interactive version of the map in iPath

  % proteins involved KEGG pathway ID Description 9.29 map04310 Wnt signaling pathway 5.71 map05219 Bladder cancer 5.71 map04060 Cytokine-cytokine receptor interaction 5.71 map05213 Endometrial cancer 5.71 map04010 MAPK signaling pathway 5.71 map05212 Pancreatic cancer 5.71 map04510 Focal adhesion 5.71 map05215 Prostate cancer 5.71 map04012 ErbB signaling pathway 5.71 map05214 Glioma 5.71 map04810 Regulation of actin cytoskeleton 5.71 map04540 Gap junction 5.71 map04340 Hedgehog signaling pathway 5.71 map05223 Non-small cell lung cancer 5.71 map05218 Melanoma 5.00 map05010 Alzheimer's disease 0.71 map00260 Glycine, serine and threonine metabolism 0.71 map00625 Tetrachloroethene degradation 0.71 map00650 Butanoate metabolism 0.71 map00591 Linoleic acid metabolism 0.71 map00052 Galactose metabolism 0.71 map00120 Bile acid biosynthesis 0.71 map00363 Bisphenol A degradation 0.71 map00051 Fructose and mannose metabolism This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with LY domain which could be assigned to a KEGG orthologous group, and not all proteins containing LY domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of LY domains in PDB

  PDB code	Main view	Title
  1ijq		Crystal structure of the ldl receptor ywtd-egf domain pair
  1n7d		Extracellular domain of the ldl receptor
  1npe		Crystal structure of nidogen/laminin complex
  1rwi		Extracellular domain of mycobacterium tuberculosis pknd
  1rwl		Extracellular domain of mycobacterium tuberculosis pknd

• Links (links to other resources describing this domain)

• PFAM	ldl_recept_b
  INTERPRO	IPR000033