人类免疫缺陷病毒(HIV-1)基质蛋白p17(p17)从感染的细胞中释放,作为能够使不同细胞的生物活性失调的蛋白质。P17变体(vp17s),更频繁地在有而不是没有淋巴瘤的HIV-1+患者的血浆中检测到,并且其特征在于其C末端区域的氨基酸插入,被发现触发B细胞生长和克隆形成。具有B细胞生长促进活性的Vp17s严重不稳定,然而,在正确折叠的状态下,参考p17(refp17)对B细胞生长和克隆形成没有任何生物活性。然而,refp17的错误折叠是暴露掩蔽的功能表位所必需的,与蛋白酶激活受体1(PAR-1)相互作用,具有B细胞克隆形成性。的确,值得注意的是,二级结构的变化可以强烈影响蛋白质的功能。这里,我们进行了计算研究,以表明vp17s的功能增益与由于二级结构元素的结构修饰和氢键(H键)网络的重排而引起的巨大构象变化有关。特别是,所有克隆vp17s都显示出两个关键残基的脱离,即Trp16和Tyr29,从它们的疏水核心。生物学数据表明,在refp17主链中,Trp16和Tyr29突变为Ala,单独或组合,产生具有B细胞克隆活性的蛋白质。这些数据显示了疏水性成分在维持refp17稳定性方面的关键作用,并确定了新的潜在治疗靶标以抵消HIV-1患者中vp17驱动的淋巴发生。
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.