The domain within your query sequence starts at position 420 and ends at position 462; the E-value for the LY domain shown below is 1.11e-3.

YTSLLPNLKNVVALDTEVTNNRIYWSDLSQKKIYSALMDQAPN

LY

Low-density lipoprotein-receptor YWTD domain

• SMART accession number: SM00135
• Description: Type "B" repeats in low-density lipoprotein (LDL) receptor that plays a central role in mammalian cholesterol metabolism. Also present in a variety of molecules similar to gp300/megalin.
• Interpro abstract (IPR000033):

  This entry represents the LDLR classB (YWTD) repeat, the structure of which has been solved [ (PUBMED:11373616) ]. The six YWTD repeats together fold into a six-bladed beta-propeller. Each blade of the propeller consists of four antiparallel beta-strands; the innermost strand of each blade is labeled 1 and the outermost strand, 4. The sequence repeats are offset with respect to the blades of the propeller, such that any given 40-residue YWTD repeat spans strands 24 of one propeller blade and strand 1 of the subsequent blade. This offset ensures circularization of the propeller because the last strand of the final sequence repeat acts as an innermost strand 1 of the blade that harbors strands 24 from the first sequence repeat. The repeat is found in a variety of proteins that include, vitellogenin receptor from Drosophila melanogaster, low-density lipoprotein (LDL) receptor [ (PUBMED:6091915) ], preproepidermal growth factor, and nidogen (entactin).

  The low-density lipoprotein receptor (LDLR) is the major cholesterol-carrying lipoprotein of plasma, acting to regulate cholesterol homeostasis in mammalian cells. The LDL receptor binds LDL and transports it into cells by acidic endocytosis. In order to be internalized, the receptor-ligand complex must first cluster into clathrin-coated pits. Once inside the cell, the LDLR separates from its ligand, which is degraded in the lysosomes, while the receptor returns to the cell surface [ (PUBMED:3513311) ]. The internal dissociation of the LDLR with its ligand is mediated by proton pumps within the walls of the endosome that lower the pH. The LDLR is a multi-domain protein, containing:

  • The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation [ (PUBMED:6091915) ]. Similar domains have been found in other extracellular and membrane proteins [ (PUBMED:7603991) ].
  • The second conserved region contains two EGF repeats, followed by six LDLR class B (YWTD) repeats, and another EGF repeat. The LDLR class B repeats each contain a conserved YWTD motif, and is predicted to form a beta-propeller structure [ (PUBMED:9790844) ]. This region is critical for ligand release and recycling of the receptor [ (PUBMED:3494949) ].
  • The third domain is rich in serine and threonine residues and contains clustered O-linked carbohydrate chains.
  • The fourth domain is the hydrophobic transmembrane region.
  • The fifth domain is the cytoplasmic tail that directs the receptor to clathrin-coated pits.

  LDLR is closely related in structure to several other receptors, including LRP1, LRP1b, megalin/LRP2, VLDL receptor, lipoprotein receptor, MEGF7/LRP4, and LRP8/apolipoprotein E receptor2); these proteins participate in a wide range of physiological processes, including the regulation of lipid metabolism, protection against atherosclerosis, neurodevelopment, and transport of nutrients and vitamins [ (PUBMED:17457719) ].

There are 128751 LY domains in 13670 proteins in SMART's nrdb database.

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

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

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 (P01130) (SMART)	OMIM:143890: Hypercholesterolemia, familial

Metabolism (metabolic pathways involving proteins which contain this domain)

% 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	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
3m0c	The X-ray Crystal Structure of PCSK9 in Complex with the LDL receptor
3p5b	The structure of the LDLR/PCSK9 complex reveals the receptor in an extended conformation
3p5c	The structure of the LDLR/PCSK9 complex reveals the receptor in an extended conformation
3s2k	Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6.
3s8v	Crystal structure of LRP6-Dkk1 complex
3s8z	Crystal structure of LRP6-E3E4
3s94	Crystal structure of LRP6-E1E2
3sob	The structure of the first YWTD beta propeller domain of LRP6 in complex with a FAB
3soq	The structure of the first YWTD beta propeller domain of LRP6 in complex with a DKK1 peptide
3sov	The structure of a beta propeller domain in complex with peptide S
3v64	Crystal Structure of agrin and LRP4
3v65	Crystal structure of agrin and LRP4 complex
3ww8	3WW8
3ww9	3WW9
3wwa	3WWA
4a0p	Crystal structure of LRP6P3E3P4E4
4dg6	Crystal structure of domains 1 and 2 of LRP6
5fww	5FWW

Links (links to other resources describing this domain)

• INTERPRO: IPR000033
• PFAM: ldl_recept_b