Amylin proprotein processing generates progressively more amyloidogenic peptides that initially sample the helical state.
Amylin proprotein processing generates progressively more amyloidogenic peptides that initially sample the helical state.
复制标题
DOI：
10.1021/bi800828u
复制
发表时间：
2008-09-16
期刊：
影响因子：
2.9
通讯作者：
Kelly, Jeffery W.
中科院分区：
文献类型：
--
作者：
Yonemoto, Isaac T.;Kroon, Gerard J. A.;Dyson, H. Jane;Balch, William E.;Kelly, Jeffery W.
人胰淀素，或胰岛淀粉样多肽，是一种由朗格汉斯胰岛的β细胞与胰岛素共同分泌的多肽。37个残基，C末端酰胺化的人胰淀素多肽来源于一个在内质网中经历二硫键形成的前蛋白，然后在未成熟的分泌颗粒中经历四次酶处理事件。人胰淀素在大多数II型糖尿病患者的胰腺中形成细胞内和细胞外的淀粉样沉积，可能反映了分泌细胞功能的受损。此外，淀粉加工中间体被认为是启动细胞内淀粉样蛋白形成的中间产物，已被报道为β细胞细胞内淀粉样蛋白的组成部分。我们在体外研究了淀粉酶及其加工中间体的淀粉样变性。变性淀粉酶和淀粉酶加工中间体经过尺寸排除层析，得到了高浓度的单体多肽。核磁共振研究表明，人胰淀素具有螺旋构象。在模拟未成熟分泌颗粒的条件下(37℃，pH 6)，淀粉蛋白形成淀粉样聚集体的速度比加工中间体更快，也比还原的淀粉样聚集体形成得更快。我们的研究还表明，淀粉及其加工中间体的淀粉样变性与净电荷和C-末端的电荷呈负相关。尽管我们的情况可能不能准确地反映体内淀粉样蛋白发生的环境，但加工中间体相对于淀粉蛋白的淀粉样原性较低，这表明它们存在于糖尿病受试者日益应激的β细胞中的细胞内淀粉样蛋白沉积中，这可能是已知的糖尿病患者蛋白质稳态控制的普遍缺陷的结果。
Human amylin, or islet amyloid polypeptide, is a peptide co-secreted with insulin by the beta cells of the pancreatic islets of Langerhans. The 37-residue, C-terminally amidated human amylin peptide derives from a proprotein that undergoes disulfide bond formation in the endoplasmic reticulum and is then subjected to four enzymatic processing events in the immature secretory granule. Human amylin forms both intracellular and extracellular amyloid deposits in the pancreas of most Type II diabetic subjects, likely reflecting compromised secretory cell function. In addition, amylin processing intermediates, postulated to initiate intracellular amyloidogenesis, have been reported as components of intracellular amyloid in beta cells. We investigated the amyloidogenicity of amylin and its processing intermediates in vitro. Chaotrope-denatured amylin and amylin processing intermediates were subjected to size exclusion chromatography, affording high concentrations of monomeric peptides. NMR studies reveal that human amylin samples helical conformations. Under conditions mimicking the immature secretory granule (37°C, pH 6), amylin forms amyloid aggregates more rapidly than its processing intermediates, and more rapidly than its reduced counterparts. Our studies also show that the amyloidogenicity of amylin and its processing intermediates is negatively correlated with net charge and charge at the C-terminus. Although our conditions may not precisely reflect the environment of amyloidogenesis in vivo, the lower amyloidogenicity of the processing intermediates relative to amylin suggests their presence in intracellular amyloid deposits in the increasingly stressed beta cells of diabetic subjects may be a consequence of general defects in protein homeostasis control known to occur in diabetes.
登录
查看更多内容
影响因子：
3.5
作者：
BETSHOLTZ, C;CHRISTMANSSON, L;WESTERMARK, P
通讯作者：
WESTERMARK, P
影响因子：
14.8
作者：
Bosco, DA;Fowler, DM;Kelly, JW
通讯作者：
Kelly, JW
影响因子：
5.6
作者：
Abedini, A;Raleigh, DP
通讯作者：
Raleigh, DP
影响因子：
2.9
作者：
Abedini, A;Singh, G;Raleigh, DP
通讯作者：
Raleigh, DP
DOI：
10.1006/bbrc.1994.2574
发表时间：
1994-11-15
影响因子：
3.1
作者：
CORT, J;LIU, ZH;ANDERSEN, NH
通讯作者：
ANDERSEN, NH