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PDBsum entry 2fcw
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protein ligands metals Protein-protein interface(s) links
Lipid transport/endocytosis/chaperone PDB id
2fcw

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
106 a.a. *
78 a.a. *
Ligands
MPD ×5
Metals
_NA ×4
_CA ×2
Waters ×179
* Residue conservation analysis
PDB id:
2fcw
Name: Lipid transport/endocytosis/chaperone
Title: Structure of a complex between the pair of the ldl receptor ligand- binding modules 3-4 and the receptor associated protein (rap).
Structure: Alpha-2-macroglobulin receptor-associated protein. Chain: a. Fragment: domain three. Synonym: alpha-2- mrap, low density lipoprotein receptor-related protein-associated protein 1, rap. Engineered: yes. Mutation: yes. Low-density lipoprotein receptor. Chain: b.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Gene: ldlr.
Biol. unit: Dimer (from PQS)
Resolution:
1.26Å     R-factor:   0.152     R-free:   0.201
Authors: N.Beglova,C.Fisher,S.C.Blacklow
Key ref:
C.Fisher et al. (2006). Structure of an LDLR-RAP complex reveals a general mode for ligand recognition by lipoprotein receptors. Mol Cell, 22, 277-283. PubMed id: 16630895 DOI: 10.1016/j.molcel.2006.02.021
Date:
12-Dec-05     Release date:   16-May-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P30533  (AMRP_HUMAN) -  Alpha-2-macroglobulin receptor-associated protein from Homo sapiens
Seq:
Struc: 		357 a.a.
106 a.a.*
Protein chain
Pfam   ArchSchema ?
P01130  (LDLR_HUMAN) -  Low-density lipoprotein receptor from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		860 a.a.
78 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 

 
DOI no: 10.1016/j.molcel.2006.02.021 Mol Cell 22:277-283 (2006)
PubMed id: 16630895  
 
 
Structure of an LDLR-RAP complex reveals a general mode for ligand recognition by lipoprotein receptors.
C.Fisher, N.Beglova, S.C.Blacklow.
 
  ABSTRACT  
 
Proteins of the low-density lipoprotein receptor (LDLR) family are remarkable in their ability to bind an extremely diverse range of protein and lipoprotein ligands, yet the basis for ligand recognition is poorly understood. Here, we report the 1.26 A X-ray structure of a complex between a two-module region of the ligand binding domain of the LDLR and the third domain of RAP, an escort protein for LDLR family members. The RAP domain forms a three-helix bundle with two docking sites, one for each LDLR module. The mode of recognition at each site is virtually identical: three conserved, calcium-coordinating acidic residues from each LDLR module encircle a lysine side chain protruding from the second helix of RAP. This metal-dependent mode of electrostatic recognition, together with avidity effects resulting from the use of multiple sites, represents a general binding strategy likely to apply in the binding of other basic ligands to LDLR family proteins.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Interface between LA3-4 and RAP-D3 		Figure 4.
Figure 4. Docking Model for ApoE Binding
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2006, 22, 277-283) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21397183 J.Chen, C.C.Liu, Q.Li, C.Nowak, G.Bu, and J.Wang (2011).
Two structural and functional domains of MESD required for proper folding and trafficking of LRP5/6.
  Structure, 19, 313-323.
PDB code: 2kgl
21337463 J.K.Lighthouse, L.Zhang, J.C.Hsieh, T.Rosenquist, and B.C.Holdener (2011).
MESD is essential for apical localization of megalin/LRP2 in the visceral endoderm.
  Dev Dyn, 240, 577-588.  
21144910 M.van den Biggelaar, E.Sellink, J.W.Klein Gebbinck, K.Mertens, and A.B.Meijer (2011).
A single lysine of the two-lysine recognition motif of the D3 domain of receptor-associated protein is sufficient to mediate endocytosis by low-density lipoprotein receptor-related protein.
  Int J Biochem Cell Biol, 43, 431-440.  
20237569 C.B.Andersen, M.Madsen, T.Storm, S.K.Moestrup, and G.R.Andersen (2010).
Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes.
  Nature, 464, 445-448.
PDB code: 3kq4
20223219 C.J.Lee, A.De Biasio, and N.Beglova (2010).
Mode of interaction between beta2GPI and lipoprotein receptors suggests mutually exclusive binding of beta2GPI to the receptors and anionic phospholipids.
  Structure, 18, 366-376.
PDB code: 2kri
20030366 M.Guttman, J.H.Prieto, J.E.Croy, and E.A.Komives (2010).
Decoding of lipoprotein-receptor interactions: properties of ligand binding modules governing interactions with apolipoprotein E.
  Biochemistry, 49, 1207-1216.  
20303980 M.Guttman, J.H.Prieto, T.M.Handel, P.J.Domaille, and E.A.Komives (2010).
Structure of the minimal interface between ApoE and LRP.
  J Mol Biol, 398, 306-319.
PDB codes: 2knx 2kny
20223215 N.Yasui, T.Nogi, and J.Takagi (2010).
Structural basis for specific recognition of reelin by its receptors.
  Structure, 18, 320-331.
PDB code: 3a7q
19674976 S.Huang, L.Henry, Y.K.Ho, H.J.Pownall, and G.Rudenko (2010).
Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor.
  J Lipid Res, 51, 297-308.  
19307174 A.Sivashanmugam, and J.Wang (2009).
A Unified Scheme for Initiation and Conformational Adaptation of Human Apolipoprotein E N-terminal Domain upon Lipoprotein Binding and for Receptor Binding Activity.
  J Biol Chem, 284, 14657-14666.  
19676115 D.Beglov, C.J.Lee, A.De Biasio, D.Kozakov, R.Brenke, S.Vajda, and N.Beglova (2009).
Structural insights into recognition of beta2-glycoprotein I by the lipoprotein receptors.
  Proteins, 77, 940-949.  
19130182 D.J.Van der Horst, S.D.Roosendaal, and K.W.Rodenburg (2009).
Circulatory lipid transport: lipoprotein assembly and function from an evolutionary perspective.
  Mol Cell Biochem, 326, 105-119.  
19397492 J.K.Jensen, K.Dolmer, C.Schar, and P.G.Gettins (2009).
Receptor-associated protein (RAP) has two high-affinity binding sites for the low-density lipoprotein receptor-related protein (LRP): consequences for the chaperone functions of RAP.
  Biochem J, 421, 273-282.  
19439404 J.K.Jensen, K.Dolmer, and P.G.Gettins (2009).
Specificity of Binding of the Low Density Lipoprotein Receptor-related Protein to Different Conformational States of the Clade E Serpins Plasminogen Activator Inhibitor-1 and Proteinase Nexin-1.
  J Biol Chem, 284, 17989-17997.  
19706701 T.Konecsni, U.Berka, A.Pickl-Herk, G.Bilek, A.G.Khan, L.Gajdzig, R.Fuchs, and D.Blaas (2009).
Low pH-triggered beta-propeller switch of the low-density lipoprotein receptor assists rhinovirus infection.
  J Virol, 83, 10922-10930.  
19767394 Z.H.Huang, R.D.Minshall, and T.Mazzone (2009).
Mechanism for endogenously expressed ApoE modulation of adipocyte very low density lipoprotein metabolism: role in endocytic and lipase-mediated metabolic pathways.
  J Biol Chem, 284, 31512-31522.  
  18626063 A.P.Lillis, L.B.Van Duyn, J.E.Murphy-Ullrich, and D.K.Strickland (2008).
LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies.
  Physiol Rev, 88, 887-918.  
18408013 C.S.Gangabadage, J.Zdunek, M.Tessari, S.Nilsson, G.Olivecrona, and S.S.Wijmenga (2008).
Structure and dynamics of human apolipoprotein CIII.
  J Biol Chem, 283, 17416-17427.
PDB code: 2jq3
18600222 G.Langer, S.X.Cohen, V.S.Lamzin, and A.Perrakis (2008).
Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7.
  Nat Protoc, 3, 1171-1179.  
18685438 N.M.Ananyeva, Y.M.Makogonenko, A.G.Sarafanov, I.V.Pechik, N.Gorlatova, K.P.Radtke, M.Shima, and E.L.Saenko (2008).
Interaction of coagulation factor VIII with members of the low-density lipoprotein receptor family follows common mechanism and involves consensus residues within the A2 binding site 484-509.
  Blood Coagul Fibrinolysis, 19, 543-555.  
18277139 N.M.Ananyeva, Y.M.Makogonenko, D.V.Kouiavskaia, J.Ruiz, V.Limburg, A.B.Meijer, A.V.Khrenov, M.Shima, D.K.Strickland, and E.L.Saenko (2008).
The binding sites for the very low density lipoprotein receptor and low-density lipoprotein receptor-related protein are shared within coagulation factor VIII.
  Blood Coagul Fibrinolysis, 19, 166-177.  
18331356 S.D.Roosendaal, J.Kerver, M.Schipper, K.W.Rodenburg, and D.J.Van der Horst (2008).
The complex of the insect LDL receptor homolog, lipophorin receptor, LpR, and its lipoprotein ligand does not dissociate under endosomal conditions.
  FEBS J, 275, 1751-1766.  
17923100 T.Yamamoto, H.W.Choi, and R.O.Ryan (2008).
Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor.
  Anal Biochem, 372, 222-226.  
18677035 Z.Zhao, and P.Michaely (2008).
The epidermal growth factor homology domain of the LDL receptor drives lipoprotein release through an allosteric mechanism involving H190, H562, and H586.
  J Biol Chem, 283, 26528-26537.  
17435765 D.Cunningham, D.E.Danley, K.F.Geoghegan, M.C.Griffor, J.L.Hawkins, T.A.Subashi, A.H.Varghese, M.J.Ammirati, J.S.Culp, L.R.Hoth, M.N.Mansour, K.M.McGrath, A.P.Seddon, S.Shenolikar, K.J.Stutzman-Engwall, L.C.Warren, D.Xia, and X.Qiu (2007).
Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia.
  Nat Struct Mol Biol, 14, 413-419.
PDB code: 2p4e
17656581 D.Lee, J.D.Walsh, M.Migliorini, P.Yu, T.Cai, C.D.Schwieters, S.Krueger, D.K.Strickland, and Y.X.Wang (2007).
The structure of receptor-associated protein (RAP).
  Protein Sci, 16, 1628-1640.
PDB codes: 2p01 2p03
17548821 N.Yasui, T.Nogi, T.Kitao, Y.Nakano, M.Hattori, and J.Takagi (2007).
Structure of a receptor-binding fragment of reelin and mutational analysis reveal a recognition mechanism similar to endocytic receptors.
  Proc Natl Acad Sci U S A, 104, 9988-9993.
PDB code: 2e26
17870468 S.C.Blacklow (2007).
Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers.
  Curr Opin Struct Biol, 17, 419-426.  
16982616 K.Dolmer, and P.G.Gettins (2006).
Three complement-like repeats compose the complete alpha2-macroglobulin binding site in the second ligand binding cluster of the low density lipoprotein receptor-related protein.
  J Biol Chem, 281, 34189-34196.  
17042782 S.Skeldal, J.V.Larsen, K.E.Pedersen, H.H.Petersen, R.Egelund, A.Christensen, J.K.Jensen, J.Gliemann, and P.A.Andreasen (2006).
Binding areas of urokinase-type plasminogen activator-plasminogen activator inhibitor-1 complex for endocytosis receptors of the low-density lipoprotein receptor family, determined by site-directed mutagenesis.
  FEBS J, 273, 5143-5159.  
17079229 V.Gupta, V.Narayanaswami, M.S.Budamagunta, T.Yamamato, J.C.Voss, and R.O.Ryan (2006).
Lipid-induced extension of apolipoprotein E helix 4 correlates with low density lipoprotein receptor binding ability.
  J Biol Chem, 281, 39294-39299.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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