3vlg

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Crystal structure of the W150A mutant LOX-1 CTLD showing impaired OxLDL binding

Structural highlights

3vlg is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

OLR1_HUMAN Note=Independent association genetic studies have implicated OLR1 gene variants in myocardial infarction susceptibility.[1] [2] [3] [4] [5] Note=OLR1 may be involved in Alzheimer disease (AD). Involvement in AD is however unclear: according to some authors (PubMed:12354387, PubMed:12810610 and PubMed:15976314), variations in OLR1 modify the risk of AD, while according to other (PubMed:15000751 and PubMed:15060104) they do not.[6] [7] [8] [9] [10]

Function

OLR1_HUMAN Receptor that mediates the recognition, internalization and degradation of oxidatively modified low density lipoprotein (oxLDL) by vascular endothelial cells. OxLDL is a marker of atherosclerosis that induces vascular endothelial cell activation and dysfunction, resulting in pro-inflammatory responses, pro-oxidative conditions and apoptosis. Its association with oxLDL induces the activation of NF-kappa-B through an increased production of intracellular reactive oxygen and a variety of pro-atherogenic cellular responses including a reduction of nitric oxide (NO) release, monocyte adhesion and apoptosis. In addition to binding oxLDL, it acts as a receptor for the HSP70 protein involved in antigen cross-presentation to naive T-cells in dendritic cells, thereby participating in cell-mediated antigen cross-presentation. Also involved in inflammatory process, by acting as a leukocyte-adhesion molecule at the vascular interface in endotoxin-induced inflammation. Also acts as a receptor for advanced glycation end (AGE) products, activated platelets, monocytes, apoptotic cells and both Gram-negative and Gram-positive bacteria.[11] [12] [13]

Publication Abstract from PubMed

Lectin-like oxidized lipoprotein (OxLDL) receptor 1, LOX-1, is the major OxLDL receptor expressed on vascular endothelial cells. We have previously reported the ligand-recognition mode of LOX-1 based on the crystal structure of the ligand binding domain (C-type lectin-like domain, CTLD) and surface plasmon resonance analysis, which suggested that the functional significance of the CTLD dimer (the 'canonical' dimer) is to harbor the characteristic "basic spine" on its surface. In this study, we have identified the key inter-domain interactions in retaining the canonical CTLD dimer by X-ray structural analysis of the inactive mutant W150A CTLD. The canonical CTLD dimer forms through tight hydrophobic interactions, in which W150 engages in a lock-and-key manner and represents the main interaction. The loss of the Trp ring by mutation to Ala prevents the formation of the canonical dimer, as elucidated from docking calculations using the crystal structure of W150A CTLD. The results emphasize that the canonically formed CTLD dimer is essential for LOX-1 to bind to OxLDL, which supports our proposed view that the basic spine surface present in the correctly formed dimer plays a primal role in OxLDL recognition. This concept provides insight into the pathogenic pattern recognized by LOX-1 as a member of the pattern recognition receptors.

Structural implication for the impaired binding of W150A mutant LOX-1 to oxidized low density lipoprotein, OxLDL.,Nakano S, Sugihara M, Yamada R, Katayanagi K, Tate SI Biochim Biophys Acta. 2012 Feb 18;1824(5):739-749. PMID:22369967[14]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Luedecking-Zimmer E, DeKosky ST, Chen Q, Barmada MM, Kamboh MI. Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer's disease on chromosome 12. Hum Genet. 2002 Oct;111(4-5):443-51. Epub 2002 Aug 16. PMID:12384789 doi:10.1007/s00439-002-0802-7
  2. ↑ Lambert JC, Luedecking-Zimmer E, Merrot S, Hayes A, Thaker U, Desai P, Houzet A, Hermant X, Cottel D, Pritchard A, Iwatsubo T, Pasquier F, Frigard B, Conneally PM, Chartier-Harlin MC, DeKosky ST, Lendon C, Mann D, Kamboh MI, Amouyel P. Association of 3'-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease. J Med Genet. 2003 Jun;40(6):424-30. PMID:12807963
  3. ↑ Bertram L, Parkinson M, Mullin K, Menon R, Blacker D, Tanzi RE. No association between a previously reported OLR1 3' UTR polymorphism and Alzheimer's disease in a large family sample. J Med Genet. 2004 Apr;41(4):286-8. PMID:15060104
  4. ↑ Pritchard A, St Clair D, Lemmon H, Mann DM, Lendon C. No association between polymorphisms in the lectin-like oxidised low density lipoprotein receptor (ORL1) gene on chromosome 12 and Alzheimer's disease in a UK cohort. Neurosci Lett. 2004 Aug 12;366(2):126-9. PMID:15276231 doi:10.1016/j.neulet.2004.05.023
  5. ↑ D'Introno A, Solfrizzi V, Colacicco AM, Capurso C, Torres F, Capurso SA, Capurso A, Panza F. Polymorphisms in the oxidized low-density lipoprotein receptor-1 gene and risk of Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 2005 Mar;60(3):280-4. PMID:15860461
  6. ↑ Luedecking-Zimmer E, DeKosky ST, Chen Q, Barmada MM, Kamboh MI. Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer's disease on chromosome 12. Hum Genet. 2002 Oct;111(4-5):443-51. Epub 2002 Aug 16. PMID:12384789 doi:10.1007/s00439-002-0802-7
  7. ↑ Lambert JC, Luedecking-Zimmer E, Merrot S, Hayes A, Thaker U, Desai P, Houzet A, Hermant X, Cottel D, Pritchard A, Iwatsubo T, Pasquier F, Frigard B, Conneally PM, Chartier-Harlin MC, DeKosky ST, Lendon C, Mann D, Kamboh MI, Amouyel P. Association of 3'-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease. J Med Genet. 2003 Jun;40(6):424-30. PMID:12807963
  8. ↑ Bertram L, Parkinson M, Mullin K, Menon R, Blacker D, Tanzi RE. No association between a previously reported OLR1 3' UTR polymorphism and Alzheimer's disease in a large family sample. J Med Genet. 2004 Apr;41(4):286-8. PMID:15060104
  9. ↑ Pritchard A, St Clair D, Lemmon H, Mann DM, Lendon C. No association between polymorphisms in the lectin-like oxidised low density lipoprotein receptor (ORL1) gene on chromosome 12 and Alzheimer's disease in a UK cohort. Neurosci Lett. 2004 Aug 12;366(2):126-9. PMID:15276231 doi:10.1016/j.neulet.2004.05.023
  10. ↑ D'Introno A, Solfrizzi V, Colacicco AM, Capurso C, Torres F, Capurso SA, Capurso A, Panza F. Polymorphisms in the oxidized low-density lipoprotein receptor-1 gene and risk of Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 2005 Mar;60(3):280-4. PMID:15860461
  11. ↑ Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, Tanaka T, Miwa S, Katsura Y, Kita T, Masaki T. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997 Mar 6;386(6620):73-7. PMID:9052782 doi:10.1038/386073a0
  12. ↑ Hayashida K, Kume N, Minami M, Kita T. Lectin-like oxidized LDL receptor-1 (LOX-1) supports adhesion of mononuclear leukocytes and a monocyte-like cell line THP-1 cells under static and flow conditions. FEBS Lett. 2002 Jan 30;511(1-3):133-8. PMID:11821063
  13. ↑ Delneste Y, Magistrelli G, Gauchat J, Haeuw J, Aubry J, Nakamura K, Kawakami-Honda N, Goetsch L, Sawamura T, Bonnefoy J, Jeannin P. Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity. 2002 Sep;17(3):353-62. PMID:12354387
  14. ↑ Nakano S, Sugihara M, Yamada R, Katayanagi K, Tate SI. Structural implication for the impaired binding of W150A mutant LOX-1 to oxidized low density lipoprotein, OxLDL. Biochim Biophys Acta. 2012 Feb 18;1824(5):739-749. PMID:22369967 doi:10.1016/j.bbapap.2012.02.003

Contents


PDB ID 3vlg

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