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Published online before print January 22, 2007, 10.1110/ps.062376207
Protein Science (2007), 16:411-419. Published by Cold Spring Harbor Laboratory Press. Copyright © 2007 The Protein Society
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The pro-peptide of proNGF: Structure formation and intramolecular association with NGF

Marco Kliemannel1, Ralph Golbik2, Rainer Rudolph1, Elisabeth Schwarz1, and Hauke Lilie1

1 Martin-Luther-Universität Halle-Wittenberg, Institut für Biotechnologie, 06120 Halle, Germany
2 Martin-Luther-Universität Halle-Wittenberg, Institut für Biochemie, 06120 Halle, Germany

(RECEIVED May 31, 2006; FINAL REVISION November 29, 2006; ACCEPTED November 30, 2006)

The pro-peptide of human nerve growth factor (NGF) functions as an intramolecular chaperone during oxidative renaturation of proNGF in vitro and interacts intramolecularly with the mature part of native proNGF. Here, we analyzed the structure formation and stability of the pro-peptide in the context of proNGF and its intramolecular interaction with the native mature part. Folding and unfolding of the NGF-coupled pro-peptide, as analyzed by fluorescence, were biphasic reactions with both phases depending on the interaction with the mature part. This interaction was characterized by an overall stability of {Delta}G = 20.9 kJ/mol that was subdivided into two reactions, native {leftrightarrow} intermediate state (14.8 kJ/mol) and intermediate {leftrightarrow} unfolded state (6.1 kJ/mol). An additional very fast unfolding reaction was observed using circular dichroism (CD), indicating the presence of at least two kinetically populated intermediates in the unfolding of proNGF. The part of the pro-peptide involved in the intramolecular association with mature NGF comprised the peptide Trp–83-Ala–63 as determined by H/D exchange experiments. Spectroscopic analyses revealed that on the NGF side, a surface area around Trp21 interacted with the pro-peptide. Trp21 also participates in binding to TrkA and p75 receptors. These overlapping binding sites of the pro-peptide and the NGF receptors might explain the previously observed lower affinity of proNGF to its receptors as compared to NGF.

Keywords: pro-peptide; proNGF; NGF; folding; receptor binding; TrkA; p75; Trp21


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