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| labmembers:the_structural_affinity_effect_of_mutational_n-glycosylation_on_vla-4_very_late_antigen_4_α4_1_integrin 2010/07/08 13:29 | labmembers:the_structural_affinity_effect_of_mutational_n-glycosylation_on_vla-4_very_late_antigen_4_α4_1_integrin 2010/07/08 13:34 current | ||
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| - | **Introduction:** Cancerous tumors often induce an inflammatory environment to promote the growth of new vascular tissue. In a typical response to such inflammations, the human immune system uses leukocytes cells to bind to the inflamed endothelial surface [[References:|(1)]]. One of the key reactions that leukocytes use to bind to the endothelial cells is the interaction between leukocyte surface integrin protein VLA-4 (very late antigen, alpha4beta1) and endothelial surface protein VCAM-1 (vascular cell adhesion molecule 1)[2, 3]. The tight binding facilitates the cell to move along the endothelial surface and migrate into the subendothelial matrix. | + | **Introduction:** Cancerous tumors often induce an inflammatory environment to promote the growth of new vascular tissue. In a typical response to such inflammations, the human immune system uses leukocytes cells to bind to the inflamed endothelial surface [1]. One of the key reactions that leukocytes use to bind to the endothelial cells is the interaction between leukocyte surface integrin protein VLA-4 (very late antigen, alpha4beta1) and endothelial surface protein VCAM-1 (vascular cell adhesion molecule 1)[2, 3]. The tight binding facilitates the cell to move along the endothelial surface and migrate into the subendothelial matrix. |
| The immune system is able to control this transendothelial migration by changing the integrin affinity state confirmation [4]. As shown in the right image, VLA-4 has three structural states: low affinity, intermediate affinity (not shown), and high affinity[5]. The increased affinity states opens binding sites MIDAS and ADMIDAS on the I domain, allowing for VCAM-1 bonding[6]. The integrin protein constantly shifts between these structures to actively change its binding capability. However the affinity state might possibly be fixed in a certain state by inserting polysaccharide glycan molecules to prevent the protein bending. While the function of the states has been studied, the control of the confirmation continues to be unknown. | The immune system is able to control this transendothelial migration by changing the integrin affinity state confirmation [4]. As shown in the right image, VLA-4 has three structural states: low affinity, intermediate affinity (not shown), and high affinity[5]. The increased affinity states opens binding sites MIDAS and ADMIDAS on the I domain, allowing for VCAM-1 bonding[6]. The integrin protein constantly shifts between these structures to actively change its binding capability. However the affinity state might possibly be fixed in a certain state by inserting polysaccharide glycan molecules to prevent the protein bending. While the function of the states has been studied, the control of the confirmation continues to be unknown. | ||
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| **References:** | **References:** | ||
| - | 1) Geng, J.G., Directional migration of leukocytes: their pathological roles in infammation and strategies for development of anti-inflammatory therapies. Cell Res, 2001. 11)2_: p85-8 | + | 1) [[http://www.nature.com/cr/journal/v11/n2/full/7290071a.html|Geng, J.G., Directional migration of leukocytes: their pathological roles in infammation and strategies for development of anti-inflammatory therapies. Cell Res, 2001. 11)2_: p85-8]] |
| - | 2) Alon R, Kassner PD, Carr MW, Finger EB, Hemler ME, and Springer TA., The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. J Cell Biol, 1995. 128(6): p1543-53 | + | 2) [[http://www.ncbi.nlm.nih.gov/pubmed/7534768|Alon R, Kassner PD, Carr MW, Finger EB, Hemler ME, and Springer TA., The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. J Cell Biol, 1995. 128(6): p1543-53]] |
| - | 3) Berlin C, Bargatze RF, Campbell JJ, von Andrian UH, Szabo MC, Hasslen SR, Nelson RD, Berg EL, Erlandsen SL, and Butcher EC., alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell, 1995. 80(3): p.413-22 | + | 3) [[http://www.ncbi.nlm.nih.gov/pubmed/7532110|Berlin C, Bargatze RF, Campbell JJ, von Andrian UH, Szabo MC, Hasslen SR, Nelson RD, Berg EL, Erlandsen SL, and Butcher EC., alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell, 1995. 80(3): p.413-22]] |
| - | 4) Luo, B.H., C.V. Carman, and T.A. Springer, Structureal basis of integrin regulation and signaling. Annu Rev Immunol, 2007. 25 p. 619-47 | + | 4) [[http://www.nature.com/nrd/journal/v2/n9/abs/nrd1174.html|Luo, B.H., C.V. Carman, and T.A. Springer, Structureal basis of integrin regulation and signaling. Annu Rev Immunol, 2007. 25 p. 619-47 |
| - | Shimaoka, M. and T.A. Springer, Therapeutic antagonists and conformational regulation of integrin function. Nat Rev Drug Discove, 2003. 2(9): p.703-16 | + | Shimaoka, M. and T.A. Springer, Therapeutic antagonists and conformational regulation of integrin function. Nat Rev Drug Discovery, 2003. 2(9): p.703-16]] |
| - | 5) Takagi J, Patre BM, Walz T, and Springer T.A., Global conformation rearrangements in integrin extracellular domains in outside-in and inside-out signalling. Cell, 2002. 110(5): p599-611 | + | 5) [[http://www.ncbi.nlm.nih.gov/pubmed/12230977|Takagi J, Patre BM, Walz T, and Springer T.A., Global conformation rearrangements in integrin extracellular domains in outside-in and inside-out signalling. Cell, 2002. 110(5): p599-611]] |
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