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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LDLa Low-density lipoprotein receptor domain class A

There are 10147 LDLa domains in 2389 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 LDLa domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with LDLa 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, Saccharomyces cerevisiae, Takifugu rubripes

• Literature (relevant references for this domain)

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

  • Varret M et al.
  • LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis.
  • Nucleic Acids Res. 1998; 26: 248-52
  • Display abstract

  • Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), a common autosomal dominant disorder. The LDLR database is a computerized tool that has been developed to provide tools to analyse the numerous mutations that have been identified in the LDLR gene. The second version of the LDLR database contains 140 new entries and the software has been modified to accommodate four new routines. The analysis of the updated data (350 mutations) gives the following informations: (i) 63% of the mutations are missense, and only 20% occur in CpG dinucleotides; (ii) although the mutations are widely distributed throughout the gene, there is an excess of mutations in exons 4 and 9, and a deficit in exons 13 and 15; (iii) the analysis of the distribution of mutations located within the ligand-binding domain shows that 74% of the mutations in this domain affect a conserved amino-acid, and that they are mostly confined in the C-terminal region of the repeats. Conversely, the same analysis in the EGF-like domain shows that 64% of the mutations in this domain affect a non-conserved amino-acid, and, that they are mostly confined in the N-terminal half of the repeats. The database is now accessible on the World Wide Web at http://www.umd.necker.fr

  • Fass D, Blacklow S, Kim PS, Berger JM
  • Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module.
  • Nature. 1997; 388: 691-3
  • Display abstract

  • The low-density lipoprotein receptor (LDLR) is responsible for the uptake of cholesterol-containing lipoprotein particles into cells. The amino-terminal region of LDLR, which consists of seven tandemly repeated, approximately 40-amino-acid, cysteine-rich modules (LDL-A modules), mediates binding to lipoproteins. LDL-A modules are biologically ubiquitous domains, found in over 100 proteins in the sequence database. The structure of ligand-binding repeat 5 (LR5) of the LDLR, determined to 1.7 A resolution by X-ray crystallography and presented here, contains a calcium ion coordinated by acidic residues that lie at the carboxy-terminal end of the domain and are conserved among LDL-A modules. Naturally occurring point mutations found in patients with the disease familial hypercholesterolaemia alter residues that directly coordinate Ca2+ or that serve as scaffolding residues of LR5.

  • Blacklow SC, Kim PS
  • Protein folding and calcium binding defects arising from familial hypercholesterolemia mutations of the LDL receptor.
  • Nat Struct Biol. 1996; 3: 758-62

  • Daly NL, Scanlon MJ, Djordjevic JT, Kroon PA, Smith R
  • Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.
  • Proc Natl Acad Sci U S A. 1995; 92: 6334-8
  • Display abstract

  • The low-density lipoprotein (LDL) receptor plays a central role in mammalian cholesterol metabolism, clearing lipoproteins which bear apolipoproteins E and B-100 from plasma. Mutations in this molecule are associated with familial hypercholesterolemia, a condition which leads to an elevated plasma cholesterol concentration and accelerated atherosclerosis. The N-terminal segment of the LDL receptor contains a heptad of cysteine-rich repeats that bind the lipoproteins. Similar repeats are present in related receptors, including the very low-density lipoprotein receptor and the LDL receptor-related protein/alpha 2-macroglobulin receptor, and in proteins which are functionally unrelated, such as the C9 component of complement. The first repeat of the human LDL receptor has been expressed in Escherichia coli as a glutathione S-transferase fusion protein, and the cleaved and purified receptor module has been shown to fold to a single, fully oxidized form that is recognized by the monoclonal antibody IgG-C7 in the presence of calcium ions. The three-dimensional structure of this module has been determined by two-dimensional NMR spectroscopy and shown to consist of a beta-hairpin structure, followed by a series of beta turns. Many of the side chains of the acidic residues, including the highly conserved Ser-Asp-Glu triad, are clustered on one face of the module. To our knowledge, this structure has not previously been described in any other protein and may represent a structural paradigm both for the other modules in the LDL receptor and for the homologous domains of several other proteins. Calcium ions had only minor effects on the CD spectrum and no effect on the 1H NMR spectrum of the repeat, suggesting that they induce no significant conformational change.

  • 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 LDLa domain.

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

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

• % proteins involved KEGG pathway ID Description 45.35 map04610 Complement and coagulation cascades 17.44 map04080 Neuroactive ligand-receptor interaction 13.95 map04310 Wnt signaling pathway 9.30 map04340 Hedgehog signaling pathway 6.98 map05010 Alzheimer's disease 5.81 map04512 ECM-receptor interaction 1.16 map04510 Focal adhesion 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 LDLa domain which could be assigned to a KEGG orthologous group, and not all proteins containing LDLa 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 LDLa domains in PDB

  PDB code	Main view	Title
  1ajj		Ldl receptor ligand-binding module 5, calcium-coordinating
  1cr8		Low density lipoprotein receptor-related protein complement repeat 8
  1d2j		Ldl receptor ligand-binding module 6
  1d2l		Nmr solution structure of complement-like repeat cr3 from the low density lipoprotein receptor-related protein (lrp) . evidence for specific binding to the receptor binding domain of human alpha-2 macroglobulin
  1f5y		Nmr structure of a concatemer of the first and second ligand-binding modules of the human ldl receptor
  1f8z		Nmr structure of the sixth ligand-binding module of the ldl receptor
  1j8e		Crystal structure of ligand-binding repeat cr7 from lrp
  1jrf		Nmr solution structure of the viral receptor domain of tva
  1k7b		Nmr solution structure of stva47, the viral-binding domain of tva
  1ldl		Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor
  1ldr		Second repeat of the ldl receptor ligand-binding domain
  1n7d		Extracellular domain of the ldl receptor
  1v9u		Human rhinovirus 2 bound to a fragment of its cellular receptor protein
  1xfe		Solution structure of the la7-egfa pair from the ldl receptor
  2fcw		Structure of a complex between the pair of the ldl receptor ligand-binding modules 3-4 and the receptor associated protein (rap).
  2fyj		Nmr solution structure of calcium-loaded lrp double module
  2fyl		Haddock model of the complex between double module of lrp, cr56, and first domain of receptor associated protein, rap- d1.
  2gtl		Lumbricus erythrocruorin at 3.5a resolution
  2i1p		Solution structure of the twelfth cysteine-rich ligand- binding repeat in rat megalin
  2jm4		The solution nmr structure of the relaxin (rxfp1) receptor ldla module.
  3dpr

• Links (links to other resources describing this domain)

• BLOCKS	LDLRA_1
  PFAM	ldl_recept_a
  INTERPRO	IPR002172