The domain within your query sequence starts at position 60 and ends at position 98; the E-value for the LDLa domain shown below is 1.41e-13.

SCSSTQFKCNSGRCIPEHWTCDGDNDCGDYSDETHANCT

LDLa

Low-density lipoprotein receptor domain class A

• SMART accession number: SM00192
• Description: Cysteine-rich repeat in the low-density lipoprotein (LDL) receptor that plays a central role in mammalian cholesterol metabolism. The N-terminal type A repeats in LDL receptor bind the lipoproteins. Other homologous domains occur 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. Mutations in the LDL receptor gene cause familial hypercholesterolemia.
• Interpro abstract (IPR002172):

  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.

  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) ].

• GO function: protein binding (GO:0005515)

There are 170761 LDLa domains in 37441 proteins in SMART's nrdb database.

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

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

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

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

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 LDLa 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
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	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.
2knx	Solution Structure of complement repeat CR17 from LRP-1
2kny	Fusion construct of CR17 from LRP-1 and ApoE residues 130-149
2kri	Structure of a complex between domain V of beta2-glycoprotein I and the fourth ligand-binding module from LDLR determined with Haddock
2lgp	Solution structure of LA45 from LDLR
2m0p	Solution structure of the tenth complement type repeat of human megalin
2m7p	RXFP1 utilises hydrophobic moieties on a signalling surface of the LDLa module to mediate receptor activation
2m96	2M96
2xrc	Human complement factor I
3a7q	Structural basis for specific recognition of reelin by its receptors
3dpr	Human rhinovirus 2 bound to a concatamer of the VLDL receptor module V3
3m0c	The X-ray Crystal Structure of PCSK9 in Complex with the LDL receptor
3ojy	Crystal Structure of Human Complement Component C8
3p5c	The structure of the LDLR/PCSK9 complex reveals the receptor in an extended conformation
3t5o	Crystal Structure of human Complement Component C6
4a5w	Crystal structure of C5b6
4e0s	Crystal Structure of C5b-6
4u8u	4U8U
4v93	4V93
4zrp	4ZRP
4zrq	4ZRQ
5f0e	5F0E
5fmw	5FMW
5h9o	5H9O
5hjo	5HJO
5hjr	5HJR
5ied	5IED
5iee	5IEE
5ief	5IEF
5ieg	5IEG
5jqp	5JQP

Links (links to other resources describing this domain)

• PFAM: ldl_recept_a
• INTERPRO: IPR002172