PDBsum entry 1xfe

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protein metals links
Lipid transport, endocytosis/exocytosis PDB id
Protein chain
83 a.a. *
_CA ×2
* Residue conservation analysis
PDB id:
Name: Lipid transport, endocytosis/exocytosis
Title: Solution structure of the la7-egfa pair from the ldl receptor
Structure: Low-density lipoprotein receptor. Chain: a. Fragment: sequence database residues 272-353: includes ldl- receptor class a 7 (residues 274-313), egf-like 1 (314- 353). Synonym: ldl receptor, la7-egfa pair. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ldlr. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Other_details: gateway expression system (invitrogen)
NMR struc: 15 models
Authors: N.Beglova,H.Jeon,C.Fisher,S.C.Blacklow
Key ref:
N.Beglova et al. (2004). Cooperation between fixed and low pH-inducible interfaces controls lipoprotein release by the LDL receptor. Mol Cell, 16, 281-292. PubMed id: 15494314 DOI: 10.1016/j.molcel.2004.09.038
14-Sep-04     Release date:   02-Nov-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P01130  (LDLR_HUMAN) -  Low-density lipoprotein receptor
860 a.a.
83 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)


DOI no: 10.1016/j.molcel.2004.09.038 Mol Cell 16:281-292 (2004)
PubMed id: 15494314  
Cooperation between fixed and low pH-inducible interfaces controls lipoprotein release by the LDL receptor.
N.Beglova, H.Jeon, C.Fisher, S.C.Blacklow.
Low-density lipoprotein (LDL) receptors bind lipoprotein particles at the cell surface and release them in the low pH environment of the endosome. The published structure of the receptor determined at endosomal pH reveals an interdomain interface between its beta propeller and its fourth and fifth ligand binding (LA) repeats, suggesting that the receptor adopts a closed conformation at low pH to release LDL. Here, we combine lipoprotein binding and release assays with NMR spectroscopy to examine structural features of the receptor promoting release of LDL at low pH. These studies lead to a model in which the receptor uses a pH-invariant scaffold as an anchor to restrict conformational search space, combining it with flexible linkers between ligand binding repeats to interconvert between open and closed conformations. This finely tuned balance between interdomain rigidity and flexibility is likely to represent a shared structural feature in proteins of the LDL receptor family.
  Selected figure(s)  
Figure 5.
Figure 5. Structure and dynamics of the LA7-EGF_A domain pair at neutral pH(A) Plot of hNOE as a function of residue number for the LA7-EGF_A pair. The hNOE profile of the LA7-EGF_A pair is the same at pH 5.2, 6.5, and 7.0, indicating the existence of an interface that does not vary with pH.(B) Best fit superposition of the 15 lowest energy neutral pH NMR structures of the LA7-EGF_A domain pair. The Cα trace and bound calcium ions are shown.(C) Ribbon trace of the LA7-EGF_A structure. The LA7 ribbon is blue, and the EGF_A ribbon is red. Disulfide bonds and calcium-coordinating side chains are illustrated in CPK colors. Bound calcium ions are yellow.(D) Close-up stereo view of the interface seen in the neutral pH NMR structure. Residues in a hydrophobic cluster that comprises the interface are labeled. Labels of residues harboring FH mutations are boxed.(E) Best fit superposition (stereo) of the neutral pH NMR structure (blue) onto the corresponding region of the crystal structure determined at endosomal pH (yellow).
Figure 7.
Figure 7. Schematic Proposing How Fixed and Flexible Connections among Domains Cooperate to Permit Interconversion between Open and Closed Conformations in Response to pHLA7, EGF_A, and EGF_B constitute a rigid scaffold that is invariant with pH. Wavy lines identify modules linked by connections likely to be flexible at the indicated pH, with freedom of movement for the ligand binding modules at neutral pH increasing as a function of distance from the rigid scaffold. LA modules are green, EGF-like modules are yellow, and the β propeller domain is pink.
  The above figures are reprinted by permission from Cell Press: Mol Cell (2004, 16, 281-292) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
20629045 R.Fuchs, and D.Blaas (2010).
Uncoating of human rhinoviruses.
  Rev Med Virol, 20, 281-297.  
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.  
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.  
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.  
19583244 Z.Zhao, and P.Michaely (2009).
The role of calcium in lipoprotein release by the low-density lipoprotein receptor.
  Biochemistry, 48, 7313-7324.  
18753623 D.W.Zhang, R.Garuti, W.J.Tang, J.C.Cohen, and H.H.Hobbs (2008).
Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor.
  Proc Natl Acad Sci U S A, 105, 13045-13050.  
18250299 H.J.Kwon, T.A.Lagace, M.C.McNutt, J.D.Horton, and J.Deisenhofer (2008).
Molecular basis for LDL receptor recognition by PCSK9.
  Proc Natl Acad Sci U S A, 105, 1820-1825.
PDB code: 3bps
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.  
18847225 T.Yamamoto, H.C.Chen, E.Guigard, C.M.Kay, and R.O.Ryan (2008).
Molecular studies of pH-dependent ligand interactions with the low-density lipoprotein receptor.
  Biochemistry, 47, 11647-11652.  
18574243 X.Arias-Moreno, A.Velazquez-Campoy, J.C.Rodríguez, M.Pocoví, and J.Sancho (2008).
Mechanism of low density lipoprotein (LDL) release in the endosome: implications of the stability and Ca2+ affinity of the fifth binding module of the LDL receptor.
  J Biol Chem, 283, 22670-22679.  
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.  
17452316 D.W.Zhang, T.A.Lagace, R.Garuti, Z.Zhao, M.McDonald, J.D.Horton, J.C.Cohen, and H.H.Hobbs (2007).
Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation.
  J Biol Chem, 282, 18602-18612.  
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.  
15952897 H.Jeon, and S.C.Blacklow (2005).
Structure and physiologic function of the low-density lipoprotein receptor.
  Annu Rev Biochem, 74, 535-562.  
15665092 L.W.Schultz, L.Liu, M.Cegielski, and J.W.Hastings (2005).
Crystal structure of a pH-regulated luciferase catalyzing the bioluminescent oxidation of an open tetrapyrrole.
  Proc Natl Acad Sci U S A, 102, 1378-1383.
PDB code: 1vpr
15950875 N.Beglova, and S.C.Blacklow (2005).
The LDL receptor: how acid pulls the trigger.
  Trends Biochem Sci, 30, 309-317.  
15718228 T.Morimura, M.Hattori, M.Ogawa, and K.Mikoshiba (2005).
Disabled1 regulates the intracellular trafficking of reelin receptors.
  J Biol Chem, 280, 16901-16908.  
15494303 R.A.Debose-Boyd (2004).
Knowing when to let go: endosomal release of LDL from the LDL-Receptor.
  Mol Cell, 16, 160-162.  
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.