A proline-rich motif downstream of the receptor binding domain modulates conformation and fusogenicity of murine retroviral envelopes
A proline-rich motif downstream of the receptor binding domain modulates conformation and fusogenicity of murine retroviral envelopes
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DOI：
10.1128/jvi.72.12.9955-9965.1998
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发表时间：
1998-12-01
影响因子：
5.4
通讯作者：
Cosset, FL
中科院分区：
文献类型：
--
作者：
Lavillette, D;Maurice, M;Cosset, FL
逆转录病毒进入细胞依赖于病毒包膜表面亚基SU的受体识别，然后是膜融合，这被认为是由位于包膜跨膜亚基TM的氨基末端的融合肽介导的。先前在小鼠白血病病毒（MLV）包膜中发现了几个融合决定因子，但它们的功能相互关系以及在逆转录病毒受体识别中参与融合激活的过程仍未阐明。尽管它们的包膜糖蛋白在结构和功能上都很相似，但生态亲和性和两性亲和性mlv表现出两种不同的结合后特性：(i)虽然两性MLV在中性pH下融合细胞，但生态型MLV的渗透相对依赖于酸性pH； （ii）生态型MLV包膜在诱导细胞间融合和合胞体形成方面比两性型包膜更有效。通过在生态型和两性型MLV包膜嵌合体的分析中利用后者的特点，我们在这里发现生态型MLV富含脯氨酸区域（PRR）的取代，位于氨基末端受体结合域和tm相互作用的SU羧基末端结构域之间的SU，足以将两性的低融合表型恢复为高融合表型。此外，我们已经确定了PRR中潜在的β -转变，其控制SU-TM关联的稳定性以及触发细胞间或病毒与细胞融合所需的阈值。这些数据表明，PRR作为诱导包膜构象变化导致融合的信号，使我们能够获得可以感染含有低水平可用两性受体的细胞的包膜。
The entry of retroviruses into cells depends on receptor recognition by the viral envelope surface subunit SU followed by membrane fusion, which is thought to be mediated by a fusion peptide located at the amino terminus of the envelope transmembrane subunit TM. Several fusion determinants have been previously identified in murine leukemia virus (MLV) envelopes, but their functional interrelationships as well as the processes involved in fusion activation upon retroviral receptor recognition remain unelucidated. Despite both structural and functional similarities of their envelope glycoproteins, ecotropic and amphotropic MLVs display two different postbinding properties: (i) while amphotropic MLVs fuse the cells at neutral pH, penetration of ecotropic MLVs is relatively acid pH dependent and (ii) ecotropic envelopes are more efficient than amphotropic envelopes in inducing cell-to-cell fusion and syncytium formation, By exploiting the latter characteristic in the analysis of chimeras of ecotropic and amphotropic MLV envelopes, we show here that substitution of the ecotropic MLV proline-rich region (PRR), located in the SU between the amino-terminal receptor binding domain and the TM-interacting SU carboxy-terminal domains, is sufficient to revert the amphotropic low-fusogenic phenotype: into a high-fusogenic one. Furthermore, we have identified potential beta-turns in the PRR that control the stability of SU-TM associations as well as the thresholds required to trigger either cell-to-cell or virus-to-cell fusion, These data, demonstrating that the PRR functions as a signal which induces envelope conformational changes leading to fusion, have enabled us to derive envelopes which can infect cells harboring low levels of available amphotropic receptors.