纤连蛋白基质形成
中文名称
通路描述
纤连蛋白（FN1）存在于所有细胞的细胞外基质（ECM）中，形成线性及分支网络，连接并包围相邻细胞（Singh et al. 2010）。在基质形成之前，FN1 以二聚体形式存在，通常代表不同的剪接变体。链间通过一对 C 端二硫键连接，这对二硫键对于后续的多聚化至关重要（Schwarzbaur 1991）。FN1 单体分子量在 230-270 kDa 之间，取决于剪接变体，包含三种重复单元 I、II 和 III。I 和 II 单元由链内二硫键稳定。III 型模块缺乏二硫键，使其在施加力时可部分解折叠（Erickson 2002）。FN1 单体全长上存在三个可变剪接区域（Mao & Schwarzbauer 2005）。细胞内 FN1 可能包含一个或两个额外的 III 型模块 EIIIA 和 EIIIB，但血浆 FN1 中不存在。在 III 型模块 14 和 15 之间存在一个可变（V）区域，这是整合素 alpha4beta1 和 alpha4beta7 的结合位点。该区域存在于大多数细胞内 FN1 中，偶尔存在于血浆 FN1 中。这些模块被组织成几个功能性和蛋白质结合域。Mao & Schwarzbauer (2005) 指出存在四个 FN1 结合域，其中域 I1-5 被称为“组装域”，对于 FN1 基质组装的启动是必需的。III9-10 对应 FN1 的“细胞结合域”。位于 III10 的 Arg-Gly-Asp (RGD) 整合素结合序列是 FN1 与细胞附着的主要位点，主要由 alpha5beta1 和 alphaVbeta3 整合素介导。III9 中的“协同位点”调节 FN1 与 alpha5beta1 整合素的结合。FN1 还包含纤维蛋白（I1-5, I10-12）、胶原蛋白（I6-9, II1-2）、纤维ulin-1（III13-14）、肝素、 syndecan（III12-14）和纤连蛋白-1（I6-9）的相互作用域（Mao & Schwartzbauer 2005, Sabatier et al. 2009）。FN1 二聚体与 alpha5beta1 整合体的结合促进自组装。结合被认为会导致 FN1 构象变化，触发进一步 FN1 二聚体的添加（Singh et al. 2010）。I1-5 作为主要的 FN1 基质组装域（Sottile et al. 1991），但其他单元也可能参与（Singh et al. 2010），该过程尚未完全理解。几种 ECM 蛋白似乎需要 FN1 基质才能进行自身组装。当纤维蛋白-1 多聚体结合到 FN1 基质时，形成纤维蛋白-1 微纤丝（Sabatier et al. 2009）。FN1 聚合促进 I 型和 III 型胶原蛋白的沉积（Sottile and Hocking 2002, Velling et al. 2002）。抑制 FN1 聚合会增加其周转率，并导致 I 型和 III 型胶原蛋白从 ECM 中损失（Sottile and Hocking 2002, Sottile et al. 2007）。FN1 由基质金属蛋白酶调节，特别是 MMP14（Shi & Sottile 2011）。
英文描述
Translation of Replicase and Assembly of the Replication Transcription Complex After entry and uncoating, the SARS-CoV-1 genomic RNA serves as a transcript to allow cap dependent translation of ORF1a to produce polyprotein pp1a. A slippery sequence and an RNA pseudoknot near the end of ORF1a enable 25 - 30% of the ribosomes to undergo -1 frameshifting, to continue translation of ORF1b to produce a longer polyprotein pp1ab. The autoproteolytic cleavage of pp1a and pp1ab generates 15-16 nonstructural proteins (nsps) with various functions. The RNA dependent RNA polymerase (RdRP) activity is encoded in nsp12, and papain like protease (PLPro) and main protease (Mpro) activities are encoded in nsp3 and nsp5, respectively. nsp3, 4, and 6 induce rearrangement of the cellular membrane to form double membrane vesicles (DMVs) where the coronavirus replication transcription complex (RTC) is assembled and anchored.
Programmed ribosomal frameshifting (PRF) may be regulated by viral or host factors in addition to viral RNA secondary structures. For example, PRF in the related arterivirus porcine reproductive and respiratory syndrome virus (PRRSV) is transactivated by the viral protein nsp1, which interacts with the PRF signal via a putative RNA binding motif. A host RNA-binding protein called annexin A2 (ANXA2) binds the pseudoknot structure in the IBV genome. Host factors in the early secretory pathway appear to be involved in DMV formation and RTC assembly: Golgi specific brefeldin A resistance guanine nucleotide exchange factor 1 (GBF1) and its effector ADP ribosylation factor 1 (ARF1) are both required for normal DMV formation and efficient RNA replication of mouse hepatitis virus (MHV), a prototypic betacoronavirus that infects mice (Fung & Liu 2019).
Programmed ribosomal frameshifting (PRF) may be regulated by viral or host factors in addition to viral RNA secondary structures. For example, PRF in the related arterivirus porcine reproductive and respiratory syndrome virus (PRRSV) is transactivated by the viral protein nsp1, which interacts with the PRF signal via a putative RNA binding motif. A host RNA-binding protein called annexin A2 (ANXA2) binds the pseudoknot structure in the IBV genome. Host factors in the early secretory pathway appear to be involved in DMV formation and RTC assembly: Golgi specific brefeldin A resistance guanine nucleotide exchange factor 1 (GBF1) and its effector ADP ribosylation factor 1 (ARF1) are both required for normal DMV formation and efficient RNA replication of mouse hepatitis virus (MHV), a prototypic betacoronavirus that infects mice (Fung & Liu 2019).
所含基因
13 个基因