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54  structures 198  species 5  interactions 19728  sequences 1237  architectures

Family: Ldl_recept_a (PF00057)

Summary: Low-density lipoprotein receptor domain class A

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This is the Wikipedia entry entitled "Low density lipoprotein receptor gene family". More...

Low density lipoprotein receptor gene family Edit Wikipedia article

Low-density lipoprotein receptor domain class A
PDB 1ldl EBI.jpg
Structure of a cysteine-rich repeat from the low-density lipoprotein receptor.[1]
Identifiers
Symbol Ldl_recept_a
Pfam PF00057
InterPro IPR002172
SMART SM00192
PROSITE PS50068
SCOP 1ldl
SUPERFAMILY 1ldl
Low-density lipoprotein receptor domain class B
PDB 1n7d EBI.jpg
Structure of the LDL receptor extracellular domain at endosomal pH.[2]
Identifiers
Symbol Ldl_recept_b
Pfam PF00058
Pfam clan 6CL0186
InterPro IPR000033
SMART SM00135
PROSITE PS51120
SCOP 1lrx
SUPERFAMILY 1lrx

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.[3] 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.[4] 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.[5][6]

There are seven members of the LDLR family in mammals, namely:

Human proteins containing this domain[edit]

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;

Examples[edit]

Listed below are human proteins containing low-density lipoprotein receptor domains:

Class A[edit]

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[edit]

EGF; LDLR; LRP1; LRP10; LRP1B; LRP2; LRP4; LRP5; LRP5L; LRP6; LRP8; NID1; NID2; SORL1; VLDLR;

See also[edit]

Structure[edit]

Modular structure of LDL receptor family members. Domains depicted hatched are differentially spliced and occur in some receptor isoforms only

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.

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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. 

External links[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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 domain class A Provide feedback

No Pfam abstract.

Literature references

  1. 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

  2. Fass D, Blacklow S, Kim PS, Berger JM; , Nature 1997;388:691-693.: Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module PUBMED:9262405 EPMC:9262405


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR002172

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 class A (cyateine-rich) repeat, which contains 6 disulphide-bound cysteines and a highly conserved cluster of negatively charged amino acids, of which many are clustered on one face of the module [PUBMED:7603991]. In LDL receptors, the class A domains form the binding site for LDL and calcium. The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLR's ligands. The repeat consists of a beta-hairpin structure followed by a series of beta turns. In the absence of calcium, LDL-A domains are unstructured; the bound calcium ion imparts structural integrity. Following these repeats is a 350 residue domain that resembles part of the epidermal growth factor (EGF) precursor. Numerous familial hypercholestorolemia mutations of the LDL receptor alter the calcium coordinating residue of LDL-A domains or other crucial scaffolding residues.

Gene Ontology

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Domain organisation

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Alignments

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(53)
Full
(19728)
Representative proteomes NCBI
(17417)
Meta
(67)
RP15
(3071)
RP35
(3990)
RP55
(7792)
RP75
(11586)
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  Seed
(53)
Full
(19728)
Representative proteomes NCBI
(17417)
Meta
(67)
RP15
(3071)
RP35
(3990)
RP55
(7792)
RP75
(11586)
Alignment:
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Sequence:
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  Seed
(53)
Full
(19728)
Representative proteomes NCBI
(17417)
Meta
(67)
RP15
(3071)
RP35
(3990)
RP55
(7792)
RP75
(11586)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

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Curation and family details

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Curation View help on the curation process

Seed source: Swissprot_feature_table
Previous IDs: ldl_recept_a;
Type: Repeat
Author: Sonnhammer ELL
Number in seed: 53
Number in full: 19728
Average length of the domain: 38.20 aa
Average identity of full alignment: 41 %
Average coverage of the sequence by the domain: 15.75 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 24.1 24.1
Trusted cut-off 24.1 24.1
Noise cut-off 24.0 24.0
Model length: 37
Family (HMM) version: 13
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Species distribution

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Interactions

There are 5 interactions for this family. More...

Rhv Ldl_recept_a EGF Globin Ldl_recept_b

Structures

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_a domain has been found. There are 54 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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