A chirality change in XPC- and Sfi1-derived peptides affects their affinity for centrin

作者：Grecu Dora; Irudayaraj Victor Paul Raj; Martinez Sanz Juan; Mallet Jean Maurice; Assairi Liliane^*

来源：Peptides, 2016, 78: 77-86.

DOI：10.1016/j.peptides.2016.02.005

• D-Peptides
• Retro-inverso peptides
• Centrin
• XPC
• Sfi1
• Isothermal titration calorimetry
• Circular dichroism

The Ca2+-binding protein centrin binds to a hydrophobic motif (W(1)xxL(4)xxxL(8)) in cluded in the sequence of several cellular targets: XPC (xeroderma pigmentosum group C protein), Sfi1 (suppressor of fermentation induced loss of stress resistance protein1), and Sac3 [the central component of the transcription and mRNA export (TREX-2) complex]. However, centrin binding occurs in a reversed orientation (L(8)xxxL(4)xxW(1)) for Sfi1 and Sac3 compared with XPC. Because D-peptides have been investigated for future therapeutic use, we analyzed their centrin-binding properties. Their affinity for centrin was measured using isothermal titration calorimetry. The chirality change in the target-derived peptides affected their ability to bind centrin in a specific manner depending on the sequence orientation of the centrin-binding motif. In contrast to L-XPC-P10, D-XPC-P10 bound C-HsCen1 in a Ca2+-dependent manner and to a lesser extent. D-XPC-P10 exhibited a reduced affinity for C-HsCen1 (K-a = 0.064 x 10(6) M-1) by a factor of 2000 compared with L-XPC-P10 (K-a = 132 x 10(6) M-1). D-peptides have a lower affinity than L-peptides for centrin, and the strength of this affinity depends on the sequence orientation of the target-derived peptides. The residual affinity observed for D-XPC suggests that the use of D-peptides represents a promising strategy for inhibiting centrin binding to its targets.

• 出版日期2016-4