Haigh Cathryn L, Tumpach Carolin, Drew Simon C, Collins Steven J
Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Melbourne Brain Centre, Melbourne, VIC, AUS, 3010.
The Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne Brain Centre, Melbourne, VIC, AUS, 3010.
PLoS One. 2015 Aug 7;10(8):e0134680. doi: 10.1371/journal.pone.0134680. eCollection 2015.
Internal cleavage of the cellular prion protein generates two well characterised N-terminal fragments, N1 and N2. These fragments have been shown to bind to anionic phospholipids at low pH. We sought to investigate binding with other lipid moieties and queried how such interactions could be relevant to the cellular functions of these fragments. Both N1 and N2 bound phosphatidylserine (PS), as previously reported, and a further interaction with phosphatidic acid (PA) was also identified. The specificity of this interaction required the N-terminus, especially the proline motif within the basic amino acids at the N-terminus, together with the copper-binding region (unrelated to copper saturation). Previously, the fragments have been shown to be protective against cellular stresses. In the current study, serum deprivation was used to induce changes in the cellular lipid environment, including externalisation of plasma membrane PS and increased cellular levels of PA. When copper-saturated, N2 could reverse these changes, but N1 could not, suggesting that direct binding of N2 to cellular lipids may be part of the mechanism by which this peptide signals its protective response.
细胞朊蛋白的内源性切割产生了两个特征明确的N端片段，即N1和N2。这些片段已被证明在低pH值下能与阴离子磷脂结合。我们试图研究它们与其他脂质部分的结合情况，并探讨这种相互作用与这些片段的细胞功能有何关联。如先前报道，N1和N2都能结合磷脂酰丝氨酸（PS），并且还发现了它们与磷脂酸（PA）的进一步相互作用。这种相互作用的特异性需要N端，特别是N端碱性氨基酸内的脯氨酸基序，以及铜结合区域（与铜饱和度无关）。此前，这些片段已被证明对细胞应激具有保护作用。在当前研究中，血清剥夺被用于诱导细胞脂质环境的变化，包括质膜PS的外化和细胞内PA水平的升高。当铜饱和时，N2可以逆转这些变化，但N1不能，这表明N2与细胞脂质的直接结合可能是该肽发出其保护反应信号的机制的一部分。
