| Structural highlights
Disease
[ITB4_HUMAN] Defects in ITGB4 are a cause of epidermolysis bullosa letalis with pyloric atresia (EB-PA) [MIM:226730]; also known as junctional epidermolysis bullosa with pyloric atresia (PA-JEB) or aplasia cutis congenita with gastrointestinal atresia. EB-PA is an autosomal recessive, frequently lethal, epidermolysis bullosa with variable involvement of skin, nails, mucosa, and with variable effects on the digestive system. It is characterized by mucocutaneous fragility, aplasia cutis congenita, and gastrointestinal atresia, which most commonly affects the pylorus. Pyloric atresia is a primary manifestation rather than a scarring process secondary to epidermolysis bullosa.[1] [2] [3] [4] [5] [6] [7] Defects in ITGB4 are a cause of generalized atrophic benign epidermolysis bullosa (GABEB) [MIM:226650]. GABEB is a non-lethal, adult form of junctional epidermolysis bullosa characterized by life-long blistering of the skin, associated with hair and tooth abnormalities.[8]
Function
[ITB4_HUMAN] Integrin alpha-6/beta-4 is a receptor for laminin. Plays a critical structural role in the hemidesmosome of epithelial cells. Is required for the regulation of keratinocyte polarity and motility.[9] [10]
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
The interaction between the integrin alpha6beta4 and plectin is essential for the assembly and stability of hemidesmosomes, which are junctional adhesion complexes that anchor epithelial cells to the basement membrane. We describe the crystal structure at 2.75 A resolution of the primary alpha6beta4-plectin complex, formed by the first pair of fibronectin type III domains and the N-terminal region of the connecting segment of beta4 and the actin-binding domain of plectin. Two missense mutations in beta4 (R1225H and R1281W) linked to nonlethal forms of epidermolysis bullosa prevent essential intermolecular contacts. We also present two structures at 1.75 and 2.05 A resolution of the beta4 moiety in the absence of plectin, which reveal a major rearrangement of the connecting segment of beta4 on binding to plectin. This conformational switch is correlated with the way alpha6beta4 promotes stable adhesion or cell migration and suggests an allosteric control of the integrin.
Structural basis of the interaction between integrin alpha6beta4 and plectin at the hemidesmosomes.,de Pereda JM, Lillo MP, Sonnenberg A EMBO J. 2009 Apr 22;28(8):1180-90. Epub 2009 Feb 26. PMID:19242489[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pulkkinen L, Rouan F, Bruckner-Tuderman L, Wallerstein R, Garzon M, Brown T, Smith L, Carter W, Uitto J. Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense. Am J Hum Genet. 1998 Nov;63(5):1376-87. PMID:9792864 doi:S0002-9297(07)61568-7
- ↑ Pulkkinen L, Kim DU, Uitto J. Epidermolysis bullosa with pyloric atresia: novel mutations in the beta4 integrin gene (ITGB4). Am J Pathol. 1998 Jan;152(1):157-66. PMID:9422533
- ↑ Pulkkinen L, Bruckner-Tuderman L, August C, Uitto J. Compound heterozygosity for missense (L156P) and nonsense (R554X) mutations in the beta4 integrin gene (ITGB4) underlies mild, nonlethal phenotype of epidermolysis bullosa with pyloric atresia. Am J Pathol. 1998 Apr;152(4):935-41. PMID:9546354
- ↑ Mellerio JE, Pulkkinen L, McMillan JR, Lake BD, Horn HM, Tidman MJ, Harper JI, McGrath JA, Uitto J, Eady RA. Pyloric atresia-junctional epidermolysis bullosa syndrome: mutations in the integrin beta4 gene (ITGB4) in two unrelated patients with mild disease. Br J Dermatol. 1998 Nov;139(5):862-71. PMID:9892956
- ↑ Kambham N, Tanji N, Seigle RL, Markowitz GS, Pulkkinen L, Uitto J, D'Agati VD. Congenital focal segmental glomerulosclerosis associated with beta4 integrin mutation and epidermolysis bullosa. Am J Kidney Dis. 2000 Jul;36(1):190-6. PMID:10873890
- ↑ Ashton GH, Sorelli P, Mellerio JE, Keane FM, Eady RA, McGrath JA. Alpha 6 beta 4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia. Br J Dermatol. 2001 Feb;144(2):408-14. PMID:11251584
- ↑ Nakano A, Pulkkinen L, Murrell D, Rico J, Lucky AW, Garzon M, Stevens CA, Robertson S, Pfendner E, Uitto J. Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatr Res. 2001 May;49(5):618-26. PMID:11328943
- ↑ Inoue M, Tamai K, Shimizu H, Owaribe K, Nakama T, Hashimoto T, McGrath JA. A homozygous missense mutation in the cytoplasmic tail of beta4 integrin, G931D, that disrupts hemidesmosome assembly and underlies Non-Herlitz junctional epidermolysis bullosa without pyloric atresia? J Invest Dermatol. 2000 May;114(5):1061-4. PMID:10792571 doi:10.1046/j.1523-1747.2000.00960-3.x
- ↑ Koster J, Geerts D, Favre B, Borradori L, Sonnenberg A. Analysis of the interactions between BP180, BP230, plectin and the integrin alpha6beta4 important for hemidesmosome assembly. J Cell Sci. 2003 Jan 15;116(Pt 2):387-99. PMID:12482924
- ↑ Hamill KJ, Hopkinson SB, DeBiase P, Jones JC. BPAG1e maintains keratinocyte polarity through beta4 integrin-mediated modulation of Rac1 and cofilin activities. Mol Biol Cell. 2009 Jun;20(12):2954-62. doi: 10.1091/mbc.E09-01-0051. Epub 2009, Apr 29. PMID:19403692 doi:10.1091/mbc.E09-01-0051
- ↑ de Pereda JM, Lillo MP, Sonnenberg A. Structural basis of the interaction between integrin alpha6beta4 and plectin at the hemidesmosomes. EMBO J. 2009 Apr 22;28(8):1180-90. Epub 2009 Feb 26. PMID:19242489 doi:10.1038/emboj.2009.48
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