Singh Pradeep K, Ghosh Dhiman, Tewari Debanjan, Mohite Ganesh M, Carvalho Edmund, Jha Narendra Nath, Jacob Reeba S, Sahay Shruti, Banerjee Rinti, Bera Amal K, Maji Samir K
Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, Maharashtra, India.
Department of Biotechnology, IIT Madras, Chennai, Tamil Nadu, India.
PLoS One. 2015 Mar 24;10(3):e0120346. doi: 10.1371/journal.pone.0120346. eCollection 2015.
Conversion of amyloid fibrils by many peptides/proteins involves cytotoxic helix-rich oligomers. However, their toxicity and biophysical studies remain largely unknown due to their highly dynamic nature. To address this, we chose two helical peptides (melittin, Mel and pancreatic polypeptide, PP) and studied their aggregation and toxicity. Mel converted its random coil structure to oligomeric helical structure upon binding to heparin; however, PP remained as helix after oligomerization. Interestingly, similar to Parkinson's associated α-synuclein (AS) oligomers, Mel and PP also showed tinctorial properties, higher hydrophobic surface exposure, cellular toxicity and membrane pore formation after oligomerization in the presence of heparin. We suggest that helix-rich oligomers with exposed hydrophobic surface are highly cytotoxic to cells irrespective of their disease association. Moreover as Mel and PP (in the presence of heparin) instantly self-assemble into stable helix-rich amyloidogenic oligomers; they could be represented as models for understanding the biophysical and cytotoxic properties of helix-rich intermediates in detail.
许多肽/蛋白质对淀粉样纤维的转化涉及富含细胞毒性螺旋的寡聚体。然而，由于其高度动态的性质，它们的毒性和生物物理研究在很大程度上仍然未知。为了解决这个问题，我们选择了两种螺旋肽（蜂毒肽，Mel和胰多肽，PP）并研究了它们的聚集和毒性。Mel与肝素结合后，其无规卷曲结构转变为寡聚螺旋结构；然而，PP在寡聚化后仍保持螺旋结构。有趣的是，与帕金森病相关的α-突触核蛋白（AS）寡聚体类似，Mel和PP在肝素存在下寡聚化后也表现出染色特性、更高的疏水表面暴露、细胞毒性和膜孔形成。我们认为，具有暴露疏水表面的富含螺旋的寡聚体对细胞具有高度细胞毒性，无论它们与疾病是否相关。此外，由于Mel和PP（在肝素存在下）能立即自组装成稳定的富含螺旋的淀粉样寡聚体；它们可以作为详细了解富含螺旋中间体的生物物理和细胞毒性特性的模型。
