Assembly assay identifies a critical region of human fibrillin-1 required for 10-12 nm diameter microfibril biogenesis.
Assembly assay identifies a critical region of human fibrillin-1 required for 10-12 nm diameter microfibril biogenesis.
复制标题
组装试验确定了10- 12nm直径微纤维生物生成所需的人纤原蛋白-1的关键区域。
DOI：
10.1371/journal.pone.0248532
复制
发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Handford PA
中科院分区：
文献类型：
--
作者：
Jensen SA;Atwa O;Handford PA
人FBN 1基因编码纤维蛋白-1（FBN 1）;直径为10-12 nm的细胞外基质微纤维的主要成分。马凡氏综合征（MFS）是一种常见的遗传性结缔组织疾病，由FBN 1突变引起。它具有广泛的疾病严重程度，从轻度病例到致命的新生儿形式（nMFS），这尚未在分子水平上解释。与nMFS相关的突变通常影响FBN 1结构域TB 3-cbEGF 18之间的区域-“新生儿区域”。为了深入了解原纤维组装的过程，并增加我们对MFS中决定疾病严重程度的机制的理解，我们比较了含有nMFS相关取代的FBN 1变体的分泌和组装特性与温和的经典MFS（cMFS）相关的变体。在大多数情况下，nMFS-和cMFS-associated新生儿区域变异体的分泌水平与野生型相当。然而，与cMFS形式相比，nMFS变体的微原纤维掺入大大减少或不存在，表明nMFS取代破坏了先前未定义的微原纤维组装位点。由外显子跳跃引起的结构域缺失变体的额外分析也表明新生儿区域中的寄存器可能对组装至关重要。这些数据首次证明了微原纤维生物发生的新要求，并确定了至少两种与TB 3-cbEGF 18区域中的疾病取代相关的不同分子机制;将突变体FBN 1掺入微原纤维中，改变其整体特性（cMFS）或通过突变分子阻断野生型FBN 1组装，从而阻止晚期侧向组装（nMFS）。
The human FBN1 gene encodes fibrillin-1 (FBN1); the main component of the 10–12 nm diameter extracellular matrix microfibrils. Marfan syndrome (MFS) is a common inherited connective tissue disorder, caused by FBN1 mutations. It features a wide spectrum of disease severity, from mild cases to the lethal neonatal form (nMFS), that is yet to be explained at the molecular level. Mutations associated with nMFS generally affect a region of FBN1 between domains TB3-cbEGF18—the "neonatal region". To gain insight into the process of fibril assembly and increase our understanding of the mechanisms determining disease severity in MFS, we compared the secretion and assembly properties of FBN1 variants containing nMFS-associated substitutions with variants associated with milder, classical MFS (cMFS). In the majority of cases, both nMFS- and cMFS-associated neonatal region variants were secreted at levels comparable to wild type. Microfibril incorporation by the nMFS variants was greatly reduced or absent compared to the cMFS forms, however, suggesting that nMFS substitutions disrupt a previously undefined site of microfibril assembly. Additional analysis of a domain deletion variant caused by exon skipping also indicates that register in the neonatal region is likely to be critical for assembly. These data demonstrate for the first time new requirements for microfibril biogenesis and identify at least two distinct molecular mechanisms associated with disease substitutions in the TB3-cbEGF18 region; incorporation of mutant FBN1 into microfibrils changing their integral properties (cMFS) or the blocking of wild type FBN1 assembly by mutant molecules that prevents late-stage lateral assembly (nMFS).
登录
查看更多内容
影响因子：
15.9
作者：
Judge, DP;Biery, NJ;Dietz, HC
通讯作者：
Dietz, HC
DOI：
10.1073/pnas.0601609103
发表时间：
2006-08-08
影响因子：
11.1
作者：
Baldock, Clair;Siegler, Veronique;Wess, Tim J.
通讯作者：
Wess, Tim J.
影响因子：
4.8
作者：
Del Cid, Joselyn S.;Reed, Nilgun Isik;Sundaram, Aparna B.
通讯作者：
Sundaram, Aparna B.
DOI：
10.1073/pnas.1401697111
发表时间：
2014-07-15
影响因子：
11.1
作者：
Jensen, Sacha A.;Aspinall, Georgia;Handford, Penny A.
通讯作者：
Handford, Penny A.
影响因子：
0.9
作者：
Yadin DA;Robertson IB;Jensen SA;Handford PA;Redfield C
通讯作者：
Redfield C