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| | <StructureSection load='5e6v' size='340' side='right'caption='[[5e6v]], [[Resolution|resolution]] 1.80Å' scene=''> | | <StructureSection load='5e6v' size='340' side='right'caption='[[5e6v]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5e6v]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5E6V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5E6V FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5e6v]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5E6V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5E6V FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1yuk|1yuk]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5e6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e6v OCA], [https://pdbe.org/5e6v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5e6v RCSB], [https://www.ebi.ac.uk/pdbsum/5e6v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5e6v ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">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=5e6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e6v OCA], [http://pdbe.org/5e6v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5e6v RCSB], [http://www.ebi.ac.uk/pdbsum/5e6v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5e6v ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ITB2_HUMAN ITB2_HUMAN]] Defects in ITGB2 are the cause of leukocyte adhesion deficiency type 1 (LAD1) [MIM:[http://omim.org/entry/116920 116920]]. LAD1 patients have recurrent bacterial infections and their leukocytes are deficient in a wide range of adhesion-dependent functions.<ref>PMID:7509236</ref> <ref>PMID:1346613</ref> <ref>PMID:1968911</ref> <ref>PMID:1694220</ref> <ref>PMID:1590804</ref> <ref>PMID:1352501</ref> <ref>PMID:1347532</ref> <ref>PMID:7686755</ref> <ref>PMID:9884339</ref> <ref>PMID:20529581</ref> <ref>PMID:20549317</ref> | + | [https://www.uniprot.org/uniprot/ITB2_HUMAN ITB2_HUMAN] Defects in ITGB2 are the cause of leukocyte adhesion deficiency type 1 (LAD1) [MIM:[https://omim.org/entry/116920 116920]. LAD1 patients have recurrent bacterial infections and their leukocytes are deficient in a wide range of adhesion-dependent functions.<ref>PMID:7509236</ref> <ref>PMID:1346613</ref> <ref>PMID:1968911</ref> <ref>PMID:1694220</ref> <ref>PMID:1590804</ref> <ref>PMID:1352501</ref> <ref>PMID:1347532</ref> <ref>PMID:7686755</ref> <ref>PMID:9884339</ref> <ref>PMID:20529581</ref> <ref>PMID:20549317</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ITB2_HUMAN 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.<ref>PMID:18587400</ref> | + | [https://www.uniprot.org/uniprot/ITB2_HUMAN 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.<ref>PMID:18587400</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | Integrins are modular (alphabeta) heterodimeric proteins that mediate cell adhesion and convey signals across the plasma membrane. Interdomain motions play a key role in signal transduction by propagating structural changes through the molecule, thus controlling the activation state and adhesive properties of the integrin. We expressed a soluble fragment of the human integrin beta2 subunit comprising the plexin-semaphorin-integrin domain (PSI)/hybrid domain/I-EGF1 fragment and present its crystal structure at 1.8-A resolution. The structure reveals an elongated molecule with a rigid architecture stabilized by nine disulfide bridges. The PSI domain is located centrally and participates in the formation of extended interfaces with the hybrid domain and I-EGF1 domains, respectively. The hybrid domain/PSI interface involves the burial of an Arg residue, and contacts between PSI and I-EGF1 are mainly mediated by well conserved Arg and Trp residues. Conservation of key interacting residues across the various integrin beta subunits sequences suggests that our structure represents a good model for the entire integrin family. Superposition with the integrin beta3 receptor in its bent conformation suggests that an articulation point is present at the linkage between its I-EGF1 and I-EGF2 modules and underlines the importance of this region for the control of integrin-mediated cell adhesion.
| + | High-resolution crystal structures of the headpiece of lymphocyte function-associated antigen-1 (integrin alphaLbeta2) reveal how the alphaI domain interacts with its platform formed by the alpha-subunit beta-propeller and beta-subunit betaI domains. The alphaLbeta2 structures compared with alphaXbeta2 structures show that the alphaI domain, tethered through its N-linker and a disulfide to a stable beta-ribbon pillar near the center of the platform, can undergo remarkable pivoting and tilting motions that appear buffered by N-glycan decorations that differ between alphaL and alphaX subunits. Rerefined beta2 integrin structures reveal details including pyroglutamic acid at the beta2 N terminus and bending within the EGF1 domain. Allostery is relayed to the alphaI domain by an internal ligand that binds to a pocket at the interface between the beta-propeller and betaI domains. Marked differences between the alphaL and alphaX subunit beta-propeller domains concentrate near the binding pocket and alphaI domain interfaces. Remarkably, movement in allostery in the betaI domain of specificity determining loop 1 (SDL1) causes concerted movement of SDL2 and thereby tightens the binding pocket for the internal ligand. |
| | | | |
| - | The crystal structure of the plexin-semaphorin-integrin domain/hybrid domain/I-EGF1 segment from the human integrin beta2 subunit at 1.8-A resolution.,Shi M, Sundramurthy K, Liu B, Tan SM, Law SK, Lescar J J Biol Chem. 2005 Aug 26;280(34):30586-93. Epub 2005 Jun 17. PMID:15965234<ref>PMID:15965234</ref> | + | Leukocyte integrin alphaLbeta2 headpiece structures: The alphaI domain, the pocket for the internal ligand, and concerted movements of its loops.,Sen M, Springer TA Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):2940-5. doi:, 10.1073/pnas.1601379113. Epub 2016 Mar 2. PMID:26936951<ref>PMID:26936951</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Sen, M]] | + | [[Category: Sen M]] |
| - | [[Category: Springer, T A]] | + | [[Category: Springer TA]] |
| - | [[Category: Cell adhesion]]
| + | |
| - | [[Category: Lfa-1]]
| + | |
| - | [[Category: Lymphocyte function-associated antigen-1]]
| + | |
| Structural highlights
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
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
High-resolution crystal structures of the headpiece of lymphocyte function-associated antigen-1 (integrin alphaLbeta2) reveal how the alphaI domain interacts with its platform formed by the alpha-subunit beta-propeller and beta-subunit betaI domains. The alphaLbeta2 structures compared with alphaXbeta2 structures show that the alphaI domain, tethered through its N-linker and a disulfide to a stable beta-ribbon pillar near the center of the platform, can undergo remarkable pivoting and tilting motions that appear buffered by N-glycan decorations that differ between alphaL and alphaX subunits. Rerefined beta2 integrin structures reveal details including pyroglutamic acid at the beta2 N terminus and bending within the EGF1 domain. Allostery is relayed to the alphaI domain by an internal ligand that binds to a pocket at the interface between the beta-propeller and betaI domains. Marked differences between the alphaL and alphaX subunit beta-propeller domains concentrate near the binding pocket and alphaI domain interfaces. Remarkably, movement in allostery in the betaI domain of specificity determining loop 1 (SDL1) causes concerted movement of SDL2 and thereby tightens the binding pocket for the internal ligand.
Leukocyte integrin alphaLbeta2 headpiece structures: The alphaI domain, the pocket for the internal ligand, and concerted movements of its loops.,Sen M, Springer TA Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):2940-5. doi:, 10.1073/pnas.1601379113. Epub 2016 Mar 2. PMID:26936951[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Sen M, Springer TA. Leukocyte integrin alphaLbeta2 headpiece structures: The alphaI domain, the pocket for the internal ligand, and concerted movements of its loops. Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):2940-5. doi:, 10.1073/pnas.1601379113. Epub 2016 Mar 2. PMID:26936951 doi:http://dx.doi.org/10.1073/pnas.1601379113
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