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==An internal ligand-bound, metastable state of a leukocyte integrin, aXb2==
==An internal ligand-bound, metastable state of a leukocyte integrin, aXb2==
<StructureSection load='4nen' size='340' side='right' caption='[[4nen]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
<StructureSection load='4nen' size='340' side='right' caption='[[4nen]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4neh|4neh]], [[3k6s|3k6s]], [[3k71|3k71]], [[3k72|3k72]], [[2iue|2iue]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4neh|4neh]], [[3k6s|3k6s]], [[3k71|3k71]], [[3k72|3k72]], [[2iue|2iue]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ITGAX, CD11C ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ITGB2, CD18, MFI7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ITGAX, CD11C ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ITGB2, CD18, MFI7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4nen FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nen OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4nen RCSB], [http://www.ebi.ac.uk/pdbsum/4nen PDBsum]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4nen FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nen OCA], [http://pdbe.org/4nen PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4nen RCSB], [http://www.ebi.ac.uk/pdbsum/4nen PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4nen ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 4nen" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==

Revision as of 00:44, 5 August 2016

An internal ligand-bound, metastable state of a leukocyte integrin, aXb2An internal ligand-bound, metastable state of a leukocyte integrin, aXb2

Structural highlights

4nen is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , , , ,
Gene:ITGAX, CD11C (HUMAN), ITGB2, CD18, MFI7 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[ITB2_HUMAN] Defects in ITGB2 are the cause of leukocyte adhesion deficiency type 1 (LAD1) [MIM:116920]. LAD1 patients have recurrent bacterial infections and their leukocytes are deficient in a wide range of adhesion-dependent functions.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

Function

[ITAX_HUMAN] Integrin alpha-X/beta-2 is a receptor for fibrinogen. It recognizes the sequence G-P-R in fibrinogen. It mediates cell-cell interaction during inflammatory responses. It is especially important in monocyte adhesion and chemotaxis. [ITB2_HUMAN] Integrin alpha-L/beta-2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4. Integrins alpha-M/beta-2 and alpha-X/beta-2 are receptors for the iC3b fragment of the third complement component and for fibrinogen. Integrin alpha-X/beta-2 recognizes the sequence G-P-R in fibrinogen alpha-chain. Integrin alpha-M/beta-2 recognizes P1 and P2 peptides of fibrinogen gamma chain. Integrin alpha-M/beta-2 is also a receptor for factor X. Integrin alpha-D/beta-2 is a receptor for ICAM3 and VCAM1. Triggers neutrophil transmigration during lung injury through PTK2B/PYK2-mediated activation.[12]

Publication Abstract from PubMed

How is massive conformational change in integrins achieved on a rapid timescale? We report crystal structures of a metastable, putative transition state of integrin alphaXbeta2. The alphaXbeta2 ectodomain is bent; however, a lattice contact stabilizes its ligand-binding alphaI domain in a high affinity, open conformation. Much of the alphaI alpha7 helix unwinds, loses contact with the alphaI domain, and reshapes to form an internal ligand that binds to the interface between the beta propeller and betaI domains. Lift-off of the alphaI domain above this platform enables a range of extensional and rotational motions without precedent in allosteric machines. Movements of secondary structure elements in the beta2 betaI domain occur in an order different than in beta3 integrins, showing that integrin beta subunits can be specialized to assume different intermediate states between closed and open. Mutations demonstrate that the structure trapped here is metastable and can enable rapid equilibration between bent and extended-open integrin conformations and up-regulation of leukocyte adhesiveness.

An internal ligand-bound, metastable state of a leukocyte integrin, alphaXbeta2.,Sen M, Yuki K, Springer TA J Cell Biol. 2013 Nov 25;203(4):629-42. doi: 10.1083/jcb.201308083. PMID:24385486[13]

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

See Also

References

  1. ↑ Ohashi Y, Yambe T, Tsuchiya S, Kikuchi H, Konno T. Familial genetic defect in a case of leukocyte adhesion deficiency. Hum Mutat. 1993;2(6):458-67. PMID:7509236 doi:http://dx.doi.org/10.1002/humu.1380020606
  2. ↑ Nelson C, Rabb H, Arnaout MA. Genetic cause of leukocyte adhesion molecule deficiency. Abnormal splicing and a missense mutation in a conserved region of CD18 impair cell surface expression of beta 2 integrins. J Biol Chem. 1992 Feb 15;267(5):3351-7. PMID:1346613
  3. ↑ Arnaout MA, Dana N, Gupta SK, Tenen DG, Fathallah DM. Point mutations impairing cell surface expression of the common beta subunit (CD18) in a patient with leukocyte adhesion molecule (Leu-CAM) deficiency. J Clin Invest. 1990 Mar;85(3):977-81. PMID:1968911 doi:http://dx.doi.org/10.1172/JCI114529
  4. ↑ Wardlaw AJ, Hibbs ML, Stacker SA, Springer TA. Distinct mutations in two patients with leukocyte adhesion deficiency and their functional correlates. J Exp Med. 1990 Jul 1;172(1):335-45. PMID:1694220
  5. ↑ Matsuura S, Kishi F, Tsukahara M, Nunoi H, Matsuda I, Kobayashi K, Kajii T. Leukocyte adhesion deficiency: identification of novel mutations in two Japanese patients with a severe form. Biochem Biophys Res Commun. 1992 May 15;184(3):1460-7. PMID:1590804
  6. ↑ Corbi AL, Vara A, Ursa A, Garcia Rodriguez MC, Fontan G, Sanchez-Madrid F. Molecular basis for a severe case of leukocyte adhesion deficiency. Eur J Immunol. 1992 Jul;22(7):1877-81. PMID:1352501 doi:http://dx.doi.org/10.1002/eji.1830220730
  7. ↑ Back AL, Kwok WW, Hickstein DD. Identification of two molecular defects in a child with leukocyte adherence deficiency. J Biol Chem. 1992 Mar 15;267(8):5482-7. PMID:1347532
  8. ↑ Back AL, Kerkering M, Baker D, Bauer TR, Embree LJ, Hickstein DD. A point mutation associated with leukocyte adhesion deficiency type 1 of moderate severity. Biochem Biophys Res Commun. 1993 Jun 30;193(3):912-8. PMID:7686755 doi:http://dx.doi.org/10.1006/bbrc.1993.1712
  9. ↑ Hogg N, Stewart MP, Scarth SL, Newton R, Shaw JM, Law SK, Klein N. A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1. J Clin Invest. 1999 Jan;103(1):97-106. PMID:9884339 doi:10.1172/JCI3312
  10. ↑ Li L, Jin YY, Cao RM, Chen TX. A novel point mutation in CD18 causing leukocyte adhesion deficiency in a Chinese patient. Chin Med J (Engl). 2010 May 20;123(10):1278-82. PMID:20529581
  11. ↑ Parvaneh N, Mamishi S, Rezaei A, Rezaei N, Tamizifar B, Parvaneh L, Sherkat R, Ghalehbaghi B, Kashef S, Chavoshzadeh Z, Isaeian A, Ashrafi F, Aghamohammadi A. Characterization of 11 new cases of leukocyte adhesion deficiency type 1 with seven novel mutations in the ITGB2 gene. J Clin Immunol. 2010 Sep;30(5):756-60. doi: 10.1007/s10875-010-9433-2. Epub 2010 , Jun 12. PMID:20549317 doi:10.1007/s10875-010-9433-2
  12. ↑ Xu J, Gao XP, Ramchandran R, Zhao YY, Vogel SM, Malik AB. Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating beta2 integrins. Nat Immunol. 2008 Aug;9(8):880-6. doi: 10.1038/ni.1628. Epub 2008 Jun 29. PMID:18587400 doi:10.1038/ni.1628
  13. ↑ Sen M, Yuki K, Springer TA. An internal ligand-bound, metastable state of a leukocyte integrin, alphaXbeta2. J Cell Biol. 2013 Nov 25;203(4):629-42. doi: 10.1083/jcb.201308083. PMID:24385486 doi:http://dx.doi.org/10.1083/jcb.201308083

4nen, resolution 2.90Å

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