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2jf1

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CRYSTAL STRUCTURE OF THE FILAMIN A REPEAT 21 COMPLEXED WITH THE INTEGRIN BETA2 CYTOPLASMIC TAIL PEPTIDECRYSTAL STRUCTURE OF THE FILAMIN A REPEAT 21 COMPLEXED WITH THE INTEGRIN BETA2 CYTOPLASMIC TAIL PEPTIDE

Structural highlights

2jf1 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:
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

[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]

Evolutionary Conservation

 

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Leukocyte integrins of the beta2 family are essential for immune cell-cell adhesion. In activated cells, beta2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the beta2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization and cell spreading. Thr758 is contained in a Thr-triplet of beta2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin and 14-3-3 proteins to phosphorylated and unphosphorylated beta2 integrins by biochemical methods and X-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (Kd 261 nM), whereas filamin bound only the unphosphorylated integrin cytoplasmic peptide (Kd 0.5 mM). Phosphorylation did not regulate talin binding to beta2 directly, but 14-3-3 was able to out-compete talin for the binding to phosphorylated beta2-integrin. X-ray crystallographic data clearly explained how phosphorylation eliminated filamin binding and induced 14-3-3 protein binding. Filamin knockdown in T cells led to an increase in stimulated cell adhesion to ICAM-1-coated surfaces. Our results suggest that the phosphorylation of beta2 integrins on Thr758 acts as a molecular switch to inhibit filamin binding and allow 14-3-3 protein binding to the integrin cytoplasmic domain, thereby modulating T cell adhesion.

Integrin {beta}2 phosphorylation on THR758 acts as a molecular switch to regulate 14-3-3 and filamin binding.,Takala H, Nurminen E, Nurmi SM, Aatonen M, Strandin T, Takatalo M, Kiema T, Gahmberg CG, Ylanne J, Fagerholm SC Blood. 2008 Jun 12;. PMID:18550856[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. ↑ Takala H, Nurminen E, Nurmi SM, Aatonen M, Strandin T, Takatalo M, Kiema T, Gahmberg CG, Ylanne J, Fagerholm SC. Integrin {beta}2 phosphorylation on THR758 acts as a molecular switch to regulate 14-3-3 and filamin binding. Blood. 2008 Jun 12;. PMID:18550856 doi:blood-2007-12-127795

2jf1, resolution 2.20Å

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