| 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]
Publication Abstract from PubMed
Integrin alpha6beta4 is a major component of hemidesmosomes that mediate the stable anchorage of epithelial cells to the underlying basement membrane. Integrin alpha6beta4 has also been implicated in cell proliferation and migration and in carcinoma progression. The third and fourth fibronectin type III domains (FnIII-3,4) of integrin beta4 mediate binding to the hemidesmosomal proteins BPAG1e and BPAG2, and participate in signalling. Here, it is demonstrated that X-ray crystallography, small-angle X-ray scattering and double electron-electron resonance (DEER) complement each other to solve the structure of the FnIII-3,4 region. The crystal structures of the individual FnIII-3 and FnIII-4 domains were solved and the relative arrangement of the FnIII domains was elucidated by combining DEER with site-directed spin labelling. Multiple structures of the interdomain linker were modelled by Monte Carlo methods complying with DEER constraints, and the final structures were selected against experimental scattering data. FnIII-3,4 has a compact and cambered flat structure with an evolutionary conserved surface that is likely to correspond to a protein-interaction site. Finally, this hybrid method is of general application for the study of other macromolecules and complexes.
Combination of X-ray crystallography, SAXS and DEER to obtain the structure of the FnIII-3,4 domains of integrin alpha6beta4.,Alonso-Garcia N, Garcia-Rubio I, Manso JA, Buey RM, Urien H, Sonnenberg A, Jeschke G, de Pereda JM Acta Crystallogr D Biol Crystallogr. 2015 Apr;71(Pt 4):969-85. doi:, 10.1107/S1399004715002485. Epub 2015 Mar 27. PMID:25849406[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Alonso-Garcia N, Garcia-Rubio I, Manso JA, Buey RM, Urien H, Sonnenberg A, Jeschke G, de Pereda JM. Combination of X-ray crystallography, SAXS and DEER to obtain the structure of the FnIII-3,4 domains of integrin alpha6beta4. Acta Crystallogr D Biol Crystallogr. 2015 Apr;71(Pt 4):969-85. doi:, 10.1107/S1399004715002485. Epub 2015 Mar 27. PMID:25849406 doi:https://dx.doi.org/10.1107/S1399004715002485
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