Molecular Determinants of Human T-cell Leukemia Virus Type 1 Gag Targeting to the Plasma Membrane for Assembly.
Molecular Determinants of Human T-cell Leukemia Virus Type 1 Gag Targeting to the Plasma Membrane for Assembly.
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人T细胞白血病病毒1型Gag靶向质膜组装的分子决定因素。
DOI：
10.1016/j.jmb.2022.167609
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发表时间：
2022-06-30
影响因子：
5.6
通讯作者：
Saad, Jamil S.
中科院分区：
文献类型：
--
作者：
Herrmann, Dominik;Hanson, Heather M.;Zhou, Lynne W.;Addabbo, Rayna;Willkomm, Nora A.;Angert, Isaac;Mueller, Joachim D.;Mansky, Louis M.;Saad, Jamil S.
关键词：
人类t细胞白血病病毒1型（HTLV-1）颗粒的组装是通过将病毒编码的Gag多蛋白运输到质膜（PM）的内小叶而启动的。Gag-PM相互作用是由基质（MA）结构域介导的，其中包含肉豆蔻酰基（myr）和赖氨酸和精氨酸残基形成的基本斑块。对于许多逆转录病毒，Gag-PM相互作用是由磷脂酰肌醇4,5-二磷酸介导的[PI(4,5)P2]；然而，先前的研究表明HTLV-1 Gag-PM相互作用和因此病毒组装较少依赖于PI(4,5)P2。我们最近发现PI(4,5)P2直接结合HTLV-1未豆芽糖酰化的MA [myr(-)MA]，磷脂酰丝氨酸（PS）和PI(4,5)P2的包合显著增强了myr(-)MA与膜的结合。在此，我们采用结构、生物物理、生化和基于细胞的分析来鉴定参与ma -膜相互作用的残基。我们的数据显示，富含赖氨酸的基序（Lys47、Lys48和Lys51）构成了PI(4,5) p2的主要结合位点。此外，我们发现位于非结构化n端的精氨酸残基3,7,14和17对于MA与含有PS和/或PI(4,5)P2的膜结合是必不可少的。证实赖氨酸和精氨酸残基都能严重减弱病毒样颗粒的产生，但只有赖氨酸残基与减少质膜结合有明显的相关性。这些结果支持了一种机制，即HTLV-1 Gag靶向PM是由myr组、富含arg和富含lys基序的三个基序参与介导的。这些发现促进了我们对逆转录病毒颗粒组装关键步骤的理解。
Assembly of human T-cell leukemia virus type 1 (HTLV-1) particles is initiated by the trafficking of virally encoded Gag polyproteins to the inner leaflet of the plasma membrane (PM). Gag–PM interactions are mediated by the matrix (MA) domain, which contains a myristoyl group (myr) and a basic patch formed by lysine and arginine residues. For many retroviruses, Gag–PM interactions are mediated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]; however, previous studies suggested that HTLV-1 Gag–PM interactions and therefore virus assembly are less dependent on PI(4,5)P2. We have recently shown that PI(4,5)P2 binds directly to HTLV-1 unmyristoylated MA [myr(–)MA] and that myr(–)MA binding to membranes is significantly enhanced by inclusion of phosphatidylserine (PS) and PI(4,5)P2. Herein, we employed structural, biophysical, biochemical, and cell-based assays to identify residues involved in MA–membrane interactions. Our data revealed that the lysine-rich motif (Lys47, Lys48, and Lys51) constitutes the primary PI(4,5)P2–binding site. Furthermore, we show that arginine residues 3, 7, 14 and 17 located in the unstructured N-terminus are essential for MA binding to membranes containing PS and/or PI(4,5)P2. Both the lysine and arginine residues were confirmed to severely attenuate virus-like particle production, but only the lysine residues could be clearly correlated with reduced plasma membrane binding. These results support a mechanism by which HTLV-1 Gag targeting to the PM is mediated by a trio engagement of the myr group, Arg-rich and Lys-rich motifs. These findings advance our understanding of a key step in retroviral particle assembly.
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