[No authors listed]
The Ca(2+)-binding protein centrin binds to a hydrophobic motif (W(1)xxL(4)xxxL(8)) included 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 Ca(2+)-dependent manner and to a lesser extent. d-XPC-P10 exhibited a reduced affinity for C-HsCen1 (Ka=0.064Ã10(6)M(-1)) by a factor of 2000 compared with l-XPC-P10 (Ka=132Ã10(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.
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