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[资源] 遗传性大疱性表皮松解症 Hereditary Epidermolysis Bullosa

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发表于 2019-1-30 00:05:07 | 显示全部楼层 |阅读模式

基因位置(人类)


更多参考表达数据

角蛋白5,也称为KRT5,K5或CK5,是由KRT5基因在人体内编码的蛋白质。[5] [6] [7] 它与角蛋白14二聚化,形成构成基底上皮细胞细胞骨架的中间丝(IF)。[8] [9] 这种蛋白质涉及多种疾病,包括大疱性表皮松解症和乳腺癌和肺癌。[9] [10] [11]

目录
1 结构
2 功能
3 临床相关性
3.1 大疱性表皮松解症
3.2 癌症
4 参考

结构
与角蛋白家族的其他成员一样,角蛋白5是中间丝蛋白。这些多肽的特征在于310残基中心杆结构域,其由通过三个短接头区(L1,L1-2和L2)连接的四个α螺旋区段(螺旋1A,1B,2A和2B)组成。[8]中心杆结构域的末端,称为螺旋起始基序(HIM)和螺旋终止基序(HTM),是高度保守的。它们对于螺旋稳定化,异二聚体形成和长丝形成尤为重要。[12]位于中心杆两侧的是可变的,非螺旋的头部和尾部区域,其从IF表面突出并为不同的IF多肽提供特异性。[8]

IF中心棒含有七肽重复序列(重复7个残基模式)的疏水性残基,允许两种不同的IF蛋白通过疏水相互作用缠绕成卷曲螺旋形成。[8]这些异二聚体在特定的I型(酸性)和II型(碱性)角蛋白对之间形成。 K5,一种II型角蛋白,与I型角蛋白K14配对。[13]卷曲螺旋二聚体经历逐步组装并以反平行方式结合,与其他卷曲螺旋形成端对端相互作用,形成大的10nm中间丝。[8] [14]

功能
角蛋白5(和K14)主要在表皮的基底角质形成细胞中表达,特别是在皮肤消化道内的分层上皮细胞中表达[9] [13]。角蛋白中间丝构成上皮细胞内的细胞骨架支架,这有助于细胞结构,并使细胞具有承受机械和非机械应力的能力。[9] [14] [15] K5 / K14角蛋白对能够进行大量的捆绑,因为K15的非螺旋尾在中间丝表面起到弱交联剂的作用。这种捆扎增加了中间长丝的弹性,从而增加了机械弹性。[15]

K5 / K14中间丝通过desmoplakin和plakophilin-1锚定在基底细胞的桥粒上,将细胞连接到它们的邻居。[16]在半桥粒中,plectin和BPAG1与跨膜蛋白α6β4整合素(一种细胞粘附分子)和BP180 /胶原XVII结合,将基底细胞中的K5 / K14细丝与基底层相连。[14]

临床意义
大疱性表皮松解症
大疱性表皮松解症(EBS)是一种遗传性皮肤水疱疾病,与K5或K14突变有关。[9] [17]引起EBS的突变主要是错义突变,但少数病例来自插入或缺失。它们的作用机制是显性负性干扰,突变的角蛋白干扰细胞骨架的结构和完整性。[9]这种细胞骨架的解体也导致半桥粒和桥粒的缺失,导致基底细胞与基底层相互失去联系。[14] [16]

已经观察到EBS的严重性取决于蛋白质内突变的位置,以及含有突变的角蛋白(K5或K14)的类型。位于中心杆结构域(HIM和HTM)两端的两个10-15个残基“热点”区域中的任一个发生的突变倾向于与更严重形式的EBS重合,而其他点的突变通常导致更温和的症状。由于“热点”区域包含α-螺旋杆的起始和终止序列,这些点的突变通常对螺旋稳定和异二聚体形成具有更大的影响。[12] [17]此外,K5突变倾向于导致比K14突变更严重的症状,可能是由于更大的空间干扰。[17]

癌症
角蛋白5可作为几种不同类型癌症的生物标志物,包括乳腺癌和肺癌。[10] [11]

由于缺乏靶向治疗,基底样乳腺癌的结果往往比其他类型的乳腺癌更差。[11] [18] [19]这些乳腺癌不表达人类表皮生长因子受体-2或雌激素或黄体酮受体,使它们对曲妥珠单抗/赫赛汀和激素疗法免疫,这些疗法对其他乳腺癌类型非常有效。由于K5表达仅见于基底细胞,因此它可作为筛查基底样乳腺癌患者的重要生物标志物,以确保它们不会接受无效治疗。[18]

对肺癌的研究还表明,鳞状细胞癌会导致K5水平升高的肿瘤,并且它们更可能来自表达K5的干细胞而非来自没有K5表达的细胞。[10] K5还可作为间皮瘤的标志物,可用于区分间皮瘤和肺腺癌[20]。 同样,它可用于区分K5阳性的乳头状瘤和K5阴性的乳头状癌[21]。 它还可以作为基底细胞癌,移行细胞癌,唾液腺肿瘤和腺瘤的标志物。[20]

K5的表达与经历上皮 - 间质转化(EMT)的细胞的中间表型相关。 该过程在肿瘤进展和转移中具有重要作用,因为它有助于使肿瘤细胞在整个身体中行进并定居远处的部位。 因此,K5可用于鉴定基底细胞转移。[22]

另见:
Intermediate filament
Keratin
Keratin 14
Cytoskeleton
Epidermolysis bullosa simplex
Basal-like carcinoma

参考:
GRCh38: Ensembl release 89: ENSG00000186081 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000061527 - Ensembl, May 2017
"Human PubMed Reference:".
"Mouse PubMed Reference:".
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Eckert RL, Rorke EA (Jun 1988). "The sequence of the human epidermal 58-kD (#5) type II keratin reveals an absence of 5' upstream sequence conservation between coexpressed epidermal keratins". Dna. 7 (5): 337–45. doi:10.1089/dna.1.1988.7.337. PMID 2456903.
Chan YM, Yu QC, LeBlanc-Straceski J, Christiano A, Pulkkinen L, Kucherlapati RS, Uitto J, Fuchs E (Apr 1994). "Mutations in the non-helical linker segment L1-2 of keratin 5 in patients with Weber-Cockayne epidermolysis bullosa simplex". Journal of Cell Science. 107 (4): 765–74. PMID 7520042.
Atkinson SD, McGilligan VE, Liao H, Szeverenyi I, Smith FJ, Moore CB, McLean WH (Oct 2011). "Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex". The Journal of Investigative Dermatology. 131 (10): 2079–86. doi:10.1038/jid.2011.169. PMID 21716320.
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Bouameur, Jamal-Eddine, et al. "Interaction of plectin with keratins 5 and 14: dependence on several plectin domains and keratin quaternary structure." Journal of Investigative Dermatology 134.11 (2014): 2776-2783.
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Intong, Lizbeth RA, and Dédée F. Murrell. "Inherited epidermolysis bullosa: new diagnostic criteria and classification." Clinics in Dermatology 30.1 (2012): 70-77.
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Further reading
Schuilenga-Hut PH, van der Vlies P, Jonkman MF, Waanders E, Buys CH, Scheffer H (Apr 2003). "Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations". Human Mutation. 21 (4): 447. doi:10.1002/humu.9124. PMID 12655565.
Seibert JA, Boone JM (Mar 2005). "X-ray imaging physics for nuclear medicine technologists. Part 2: X-ray interactions and image formation". Journal of Nuclear Medicine Technology. 33 (1): 3–18. PMID 15731015.
Ohtsuki M, Tomic-Canic M, Freedberg IM, Blumenberg M (Nov 1992). "Regulation of epidermal keratin expression by retinoic acid and thyroid hormone". The Journal of Dermatology. 19 (11): 774–80. doi:10.1111/j.1346-8138.1992.tb03779.x. PMID 1284070.
Lane EB, Rugg EL, Navsaria H, Leigh IM, Heagerty AH, Ishida-Yamamoto A, Eady RA (Mar 1992). "A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering". Nature. 356 (6366): 244–6. doi:10.1038/356244a0. PMID 1372711.
Tavakkol A, Griffiths CE, Keane KM, Palmer RD, Voorhees JJ (Aug 1992). "Cellular localization of mRNA for cellular retinoic acid-binding protein II and nuclear retinoic acid receptor-gamma 1 in retinoic acid-treated human skin". The Journal of Investigative Dermatology. 99 (2): 146–50. doi:10.1111/1523-1747.ep12616781. PMID 1378478.
Rosenberg M, Fuchs E, Le Beau MM, Eddy RL, Shows TB (1991). "Three epidermal and one simple epithelial type II keratin genes map to human chromosome 12". Cytogenetics and Cell Genetics. 57 (1): 33–8. doi:10.1159/000133109. PMID 1713141.
Ryynänen M, Knowlton RG, Uitto J (Nov 1991). "Mapping of epidermolysis bullosa simplex mutation to chromosome 12". American Journal of Human Genetics. 49 (5): 978–84. PMC 1683248. PMID 1718160.
Bonifas JM, Rothman AL, Epstein EH (Nov 1991). "Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities". Science. 254 (5035): 1202–5. doi:10.1126/science.1720261. PMID 1720261.
Lersch R, Fuchs E (Jan 1988). "Sequence and expression of a type II keratin, K5, in human epidermal cells". Molecular and Cellular Biology. 8 (1): 486–93. doi:10.1128/mcb.8.1.486. PMC 363157. PMID 2447486.
Galup C, Darmon MY (Jul 1988). "Isolation and characterization of a cDNA clone coding for human epidermal keratin K5. Sequence of the carboxyterminal half of this keratin". The Journal of Investigative Dermatology. 91 (1): 39–42. doi:10.1111/1523-1747.ep12463286. PMID 2455002.
Eckert RL, Rorke EA (Jun 1988). "The sequence of the human epidermal 58-kD (#5) type II keratin reveals an absence of 5' upstream sequence conservation between coexpressed epidermal keratins". Dna. 7 (5): 337–45. doi:10.1089/dna.1.1988.7.337. PMID 2456903.
Lersch R, Stellmach V, Stocks C, Giudice G, Fuchs E (Sep 1989). "Isolation, sequence, and expression of a human keratin K5 gene: transcriptional regulation of keratins and insights into pairwise control". Molecular and Cellular Biology. 9 (9): 3685–97. doi:10.1128/mcb.9.9.3685. PMC 362429. PMID 2476664.
Rugg EL, Morley SM, Smith FJ, Boxer M, Tidman MJ, Navsaria H, Leigh IM, Lane EB (Nov 1993). "Missing links: Weber-Cockayne keratin mutations implicate the L12 linker domain in effective cytoskeleton function". Nature Genetics. 5 (3): 294–300. doi:10.1038/ng1193-294. PMID 7506097.
Kouklis PD, Hutton E, Fuchs E (Nov 1994). "Making a connection: direct binding between keratin intermediate filaments and desmosomal proteins". The Journal of Cell Biology. 127 (4): 1049–60. doi:10.1083/jcb.127.4.1049. PMC 2200061. PMID 7525601.
Stephens K, Zlotogorski A, Smith L, Ehrlich P, Wijsman E, Livingston RJ, Sybert VP (Mar 1995). "Epidermolysis bullosa simplex: a keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton function". American Journal of Human Genetics. 56 (3): 577–85. PMC 1801159. PMID 7534039.
Ehrlich P, Sybert VP, Spencer A, Stephens K (May 1995). "A common keratin 5 gene mutation in epidermolysis bullosa simplex--Weber-Cockayne". The Journal of Investigative Dermatology. 104 (5): 877–9. doi:10.1111/1523-1747.ep12607050. PMID 7537780.
Wanner R, Förster HH, Tilmans I, Mischke D (Jun 1993). "Allelic variations of human keratins K4 and K5 provide polymorphic markers within the type II keratin gene cluster on chromosome 12". The Journal of Investigative Dermatology. 100 (6): 735–41. doi:10.1111/1523-1747.ep12475671. PMID 7684424.
Dong W, Ryynänen M, Uitto J (1993). "Identification of a leucine-to-proline mutation in the keratin 5 gene in a family with the generalized Köbner type of epidermolysis bullosa simplex". Human Mutation. 2 (2): 94–102. doi:10.1002/humu.1380020206. PMID 7686424.
Chan YM, Yu QC, Fine JD, Fuchs E (Aug 1993). "The genetic basis of Weber-Cockayne epidermolysis bullosa simplex". Proceedings of the National Academy of Sciences of the United States of America. 90 (15): 7414–8. doi:10.1073/pnas.90.15.7414. PMC 47148. PMID 7688477.

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