Summary: Low-density lipoprotein receptor repeat class B
This is the Wikipedia entry entitled "Low density lipoprotein receptor gene family". More...
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Low density lipoprotein receptor gene family Edit Wikipedia article
|Low-density lipoprotein receptor domain class A|
|Structure of a cysteine-rich repeat from the low-density lipoprotein receptor.|
|Low-density lipoprotein receptor domain class B|
|Structure of the LDL receptor extracellular domain at endosomal pH.|
The low density lipoprotein receptor gene family codes for a class of structurally related cell surface receptors that fulfill diverse biological functions in different organs, tissues, and cell types. The role that is most commonly associated with this evolutionarily ancient family is cholesterol homeostasis (maintenance of appropriate concentration of cholesterol). In humans, excess cholesterol in the blood is captured by low-density lipoprotein (LDL) and removed by the liver via endocytosis of the LDL receptor. Recent evidence indicates that the members of the LDL receptor gene family are active in the cell signalling pathways between specialized cells in many, if not all, multicellular organisms.
There are seven members of the LDLR family in mammals, namely:
- VLDL receptor (VLDLR)
- ApoER2, or LRP8
- Multiple epidermal growth factor (EGF) repeat-containing protein (MEGF7)
- LDLR-related protein 1
- LDLR-related protein 1b
 Human proteins containing this domain
Complement component 6; Complement component 7; Complement component 8A; Complement component 8B; Complement component 9; CD320; CFI; CORIN; DGCR2; HSPG2; LDLR; LDLRAD2; LDLRAD3; LRP1; LRP10; LRP11; LRP12; LRP1B; LRP2; LRP3; LRP4; LRP5; LRP6; LRP8; MAMDC4; MFRP; PRSS7; RXFP1; RXFP2; SORL1; SPINT1; SSPO; ST14; TMPRSS4; TMPRSS6; TMPRSS7; TMPRSS9; VLDLR; serase-1B;
Listed below are human proteins containing low-density lipoprotein receptor domains:
 Class A
C6; C7; 8A; 8B; C9; CD320; CFI; CORIN; DGCR2; HSPG2; LDLR; LDLRAD2; LDLRAD3; LRP1; LRP10; LRP11; LRP12; LRP1B; LRP2; LRP3; LRP4; LRP5; LRP6; LRP8; MAMDC4; MFRP; PRSS7; RXFP1; RXFP2; SORL1; SPINT1; SSPO; ST14; TMPRSS4; TMPRSS6; TMPRSS7; TMPRSS9; VLDLR;
 Class B
 See also
- Soluble low density lipoprotein receptor-related protein (sLRP) - impaired function is related to Alzheimer's Disease.
The members of the LDLR family are characterized by distinct functional domains present in characteristic numbers. These modules are:
- LDL receptor type A (LA) repeats of 40 residues each, displaying a triple-disulfide-bond-stabilized negatively charged surface; certain head-to-tail combinations of these repeats are believed to specify ligand interactions;
- LDL receptor type B repeats, also known as EGF precursor homology regions, containing EGF-like repeats and YWTD beta propeller domains;
- a transmembrane domain, and
- the cytoplasmic region with (a) signal(s) for receptor internalization via coated pits, containing the consensus tetrapeptide Asn-Pro-Xaa-Tyr (NPxY). This cytoplasmic tail controls both endocytosis and signaling by interacting with the phosphotyrosine binding (PTB) domain-containing proteins.
In addition to these domains which can be found in all receptors of the gene family, LDL receptor and certain isoforms of ApoER2 and VLDLR contain a short region which can undergo O-linked glycosylation, known as O-linked sugar domain. ApoER2 moreover, can harbour a cleavage site for the protease furin between type A and type B repeats which enables production of a soluble receptor fragment by furin-mediated processing.
- Daly NL, Scanlon MJ, Djordjevic JT, Kroon PA, Smith R (July 1995). "Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor". Proc. Natl. Acad. Sci. U.S.A. 92 (14): 6334–8. doi:10.1073/pnas.92.14.6334. PMC 41512. PMID 7603991. //www.ncbi.nlm.nih.gov/pmc/articles/PMC41512/.
- Rudenko G, Henry L, Henderson K, et al. (December 2002). "Structure of the LDL receptor extracellular domain at endosomal pH". Science 298 (5602): 2353–8. doi:10.1126/science.1078124. PMID 12459547.
- Nykjaer A, Willnow TE (June 2002). "The low-density lipoprotein receptor gene family: a cellular Swiss army knife?". Trends Cell Biol. 12 (6): 273–80. doi:10.1016/S0962-8924(02)02282-1. PMID 12074887. http://linkinghub.elsevier.com/retrieve/pii/S0962892402022821.
- Li Y, Lu W, Marzolo MP, Bu G (May 2001). "Differential functions of members of the low density lipoprotein receptor family suggested by their distinct endocytosis rates". J. Biol. Chem. 276 (21): 18000–6. doi:10.1074/jbc.M101589200. PMID 11279214.
- Gotthardt M, Trommsdorff M, Nevitt MF, Shelton J, Richardson JA, Stockinger W, Nimpf J, Herz J (August 2000). "Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction". J. Biol. Chem. 275 (33): 25616–24. doi:10.1074/jbc.M000955200. PMID 10827173.
- Beffert U, Stolt PC, Herz J (March 2004). "Functions of lipoprotein receptors in neurons". J. Lipid Res. 45 (3): 403–9. doi:10.1194/jlr.R300017-JLR200. PMID 14657206.
- Schematic representation of the seven mammalian LDL receptor (LDLR) family members
- LDL receptor family members
- LDL Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Low-density lipoprotein receptor repeat class B Provide feedback
This domain is also known as the YWTD motif after the most conserved region of the repeat. The YWTD repeat is found in multiple tandem repeats and has been predicted to form a beta-propeller structure .
Yamamoto T, Davis CG, Brown MS, Schneider WJ, Casey ML, Goldstein JL, Russell DW; , Cell 1984;39:27-38.: The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. PUBMED:6091915 EPMC:6091915
Springer TA; , J Mol Biol 1998;283:837-862.: An Extracellular beta-Propeller Module Predicted in Lipoprotein and Scavenger Receptors, Tyrosine Kinases, Epidermal Growth Factor Precursor, and Extracellular Matrix Components. PUBMED:9790844 EPMC:9790844
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000033
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].
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).
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Curation and family details
|Author:||Bateman A, Sonnhammer ELL|
|Number in seed:||28|
|Number in full:||8618|
|Average length of the domain:||41.70 aa|
|Average identity of full alignment:||31 %|
|Average coverage of the sequence by the domain:||14.93 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||12|
|Download:||download the raw HMM for this family|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Ldl_recept_b domain has been found. There are 112 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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