Institute of Technologies in Biomedicine, National Research Council, 20090 Segrate, Italy.
Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Viruses. 2024 Jun 28;16(7):1048. doi: 10.3390/v16071048.
The human immunodeficiency virus (HIV-1) matrix protein p17 (p17) is released from infected cells as a protein capable of deregulating the biological activity of different cells. P17 variants (vp17s), more frequently detected in the plasma of HIV-1 patients with rather than without lymphoma and characterized by amino acids insertions in their C-terminal region, were found to trigger B cell growth and clonogenicity. Vp17s endowed with B-cell-growth-promoting activity are drastically destabilized, whereas, in a properly folded state, reference p17 (refp17) does not exert any biological activity on B cell growth and clonogenicity. However, misfolding of refp17 is necessary to expose a masked functional epitope, interacting with the protease-activated receptor 1 (PAR-1), endowed with B cell clonogenicity. Indeed, it is worth noting that changes in the secondary structure can strongly impact the function of a protein. Here, we performed computational studies to show that the gain of function of vp17s is linked to dramatic conformational changes due to structural modification in the secondary-structure elements and in the rearrangement of the hydrogen bond (H-bond) network. In particular, all clonogenic vp17s showed the disengagement of two critical residues, namely Trp16 and Tyr29, from their hydrophobic core. Biological data showed that the mutation of Trp16 and Tyr29 to Ala in the refp17 backbone, alone or in combination, resulted in a protein endowed with B cell clonogenic activity. These data show the pivotal role of the hydrophobic component in maintaining refp17 stability and identify a novel potential therapeutic target to counteract vp17-driven lymphomagenesis in HIV-1 patients.
人类免疫缺陷病毒 1 型（HIV-1）的基质蛋白 p17（p17）从受感染的细胞中释放出来，成为一种能够调节不同细胞生物活性的蛋白质。在 HIV-1 患者的血浆中，更频繁地检测到 p17 的变异体（vp17s），其 C 末端区域有氨基酸插入，被发现能触发 B 细胞的生长和集落形成。具有促进 B 细胞生长活性的 vp17s 严重不稳定，而参考 p17（refp17）在适当折叠的状态下，对 B 细胞的生长和集落形成没有任何生物学活性。然而，refp17 的错误折叠是暴露一个被掩盖的功能性表位所必需的，该表位与蛋白酶激活受体 1（PAR-1）相互作用，具有 B 细胞集落形成能力。事实上，值得注意的是，二级结构的变化会强烈影响蛋白质的功能。在这里，我们进行了计算研究，表明 vp17s 的功能获得与由于二级结构元件的结构修饰和氢键（H-bond）网络的重新排列而导致的剧烈构象变化有关。特别是，所有具有集落形成能力的 vp17s 都显示出两个关键残基，即色氨酸 16 和酪氨酸 29，从其疏水性核心脱离。生物学数据表明，refp17 骨架中色氨酸 16 和酪氨酸 29 突变为丙氨酸，单独或组合使用，会导致具有 B 细胞集落形成活性的蛋白质。这些数据表明疏水性成分在维持 refp17 稳定性方面的关键作用，并确定了一个新的潜在治疗靶点，以对抗 HIV-1 患者中由 vp17 驱动的淋巴瘤发生。
