Identification of folding preferences of cleavage junctions of HIV-1 precursor proteins for regulation of cleavability
Identification of folding preferences of cleavage junctions of HIV-1 precursor proteins for regulation of cleavability
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DOI：
10.1007/s00894-010-0739-z
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发表时间：
2011-02-01
影响因子：
2.2
通讯作者：
Sato, Hironori
中科院分区：
文献类型：
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作者：
Ode, Hirotaka;Yokoyama, Masaru;Sato, Hironori
人类免疫缺陷病毒1型蛋白酶（HIV-1 PR）在多个位点切割两种病毒前体蛋白，Gag和Gag- pol。虽然这个过程是按等级顺序进行的，以确保有效的病毒复制，但这种顺序被调节的分子机制还不完全清楚。在本研究中，我们利用生物信息学方法研究了切割连接的折叠偏好是否会影响HIV-1 PR的切割能力。利用分子动力学和同源性建模方法模拟了HIV-1(HXB2) Gag和Gag- pol前体的7个切割连接对应的8个氨基酸肽在PR-自由和PR-结合状态下的折叠。分析了HIV-1（HXB2）肽的折叠参数与已报道的动力学参数之间的关系。我们发现，在无pr状态下，C β (P1)-C α (P1)-C α （P1′）-C β （P1′）在150 ~ 180度范围内形成二面角的折叠偏好与1/K(m)呈正相关（R = 0.95, P = 0.0008），而在pr结合状态下，主链的O (P2)-C (P2)-C (P1)- O （P1）的二面角与K（cat）呈负相关（R = 0.94, P = 0.001）。我们进一步发现，当P1位点侧链的大小相似时，这两种折叠特性会影响前体蛋白的整体可切割性。这些数据表明，在与PR结合前后，切割连接点周围特定位置的二面角对HIV-1 PR调节前体蛋白的切割能力都是至关重要的。
Human immunodeficiency virus type 1 protease (HIV-1 PR) cleaves two viral precursor proteins, Gag and Gag-Pol, at multiple sites. Although the processing proceeds in the rank order to assure effective viral replication, the molecular mechanisms by which the order is regulated are not fully understood. In this study, we used bioinformatics approaches to examine whether the folding preferences of the cleavage junctions influence their cleavabilities by HIV-1 PR. The folding of the eight-amino-acid peptides corresponding to the seven cleavage junctions of the HIV-1(HXB2) Gag and Gag-Pol precursors were simulated in the PR-free and PR-bound states with molecular dynamics and homology modeling methods, and the relationships between the folding parameters and the reported kinetic parameters of the HIV-1(HXB2) peptides were analyzed. We found that a folding preference for forming a dihedral angle of C beta (P1)-C alpha (P1)- C alpha (P1')-C beta (P1') in the range of 150 to 180 degrees in the PR-free state was positively correlated with the 1/K(m) (R = 0.95, P = 0.0008) and that the dihedral angle of the O (P2)-C (P2)- C (P1)- O (P1) of the main chains in the PR-bound state was negatively correlated with k(cat) (R = 0.94, P = 0.001). We further found that these two folding properties influenced the overall cleavability of the precursor protein when the sizes of the side chains at the P1 site were similar. These data suggest that the dihedral angles at the specific positions around the cleavage junctions before and after binding to PR are both critical for regulating the cleavability of precursor proteins by HIV-1 PR.