Role of the conformational versatility of the neurotrophin N-terminal regions in their recognition by Trk receptors(455 views) Stanzione F, Esposito L, Paladino A, Pedone C, Morelli G, Vitagliano L
Biophysical Journal (ISSN: 1542-0086, 0006-3495), 2010 Oct 6; 99(7): 2273-2278.
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Recerche, Naples, Italy.
Sezione di Biostrutture, Dipartimento Delle Scienze Biologiche, Università Degli Studi di Napoli Federico II, Naples, Italy
Laboratorio di Bioinformatica e Biologia Molecolare, Istituto di Scienze Alimentari, CNR, Avellino, Italy
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Colangelo, A. M., Bianco., M. R., Martegani, E., A new nerve growth factor-mimetic peptide active on neuropathic pain in rats (2008) J. Neurosci., 28, pp. 2698-2709
Saragovi, H. U., Hamel, E., Di Polo, A., A neurotrophic rationale for the therapy of neurodegenerative disorders (2009) Curr. Alzheimer Res., 6, pp. 419-423
O'Leary, P. D., Hughes, R. A., Design of potent peptide mimetics of brain-derived neurotrophic factor (2003) J. Biol. Chem., 278, pp. 25738-25744
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Massa, S. M., Xie, Y., Longo, F. M., Alzheimer's therapeutics: Neurotrophin small molecule mimetics (2002) J. Mol. Neurosci., 19, pp. 107-111
Bruno, M. A., Clarke., P. B., Saragovi, H. U., Long-lasting rescue of age-associated deficits in cognition and the CNS cholinergic phenotype by a partial agonist peptidomimetic ligand of TrkA (2004) J. Neurosci., 24, pp. 8009-8018
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Blundell, T. L., Burke., D. F., Sibanda, B. L., Protein-protein interactions in receptor activation and intracellular signalling (2000) Biol. Chem., 381, pp. 955-959
He., W. X. T., Garcia, K. C., Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors (2007) Neuron, 53, pp. 25-38
He, X. L., Garcia, K. C., Structure of nerve growth factor complexed with the shared neurotrophin receptor p75 (2004) Science, 304, pp. 870-875
Banfield, M. J., Naylor., R. L., Brady, R. L., Specificity in Trk receptor: neurotrophin interactions: The crystal structure of TrkB-d5 in complex with neurotrophin-4/5 (2001) Structure, 9, pp. 1191-1199
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Walensky, L. D., Kung., A. L., Korsmeyer, S. J., Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix (2004) Science, 305, pp. 1466-1470
Ma, N., Wu., S. S., Wang, S., Nerve growth factor receptormediated gene transfer (2004) Mol. Ther., 9, pp. 270-281
Role of the conformational versatility of the neurotrophin N-terminal regions in their recognition by Trk receptors
Neurotrophins (NTs) represent a family of proteins that play an important role in the survival, development, and function of neurons. Extensive efforts are currently being made to develop small molecules endowed with agonist or antagonist NT activity. The structurally versatile N-termini of these proteins are considered regions of interest for the design of new molecules. By combining experimental and computational approaches, we analyzed the intrinsic conformational preferences of the N-termini of two of the most important NTs: NGF (NGF-Nter) and NT4 (NT4-Nter). Circular dichroism spectra clearly indicate that both peptides show a preference for random coil states. Because this finding does not preclude the possibility that structured forms may occur in solution as minor conformational states, we performed molecular-dynamics simulations to gain insights into the structural features of populated species. In line with the circular dichroism analysis, the simulations show a preference for unstructured states for both peptides. However, the simulations also show that for NT4-Nter, and to a lesser extent for NGF-Nter, helical conformations, which are required for binding to the Trk receptor, are present in the repertoire of structures that are intrinsically accessible to these peptides. Accordingly, molecular recognition of NTs by the Trk receptor is accomplished by the general mechanism known as population shift. These findings provide a structural rationale for the observed activity of synthetic peptides based on these NT regions. They also suggest strategies for the development of biologically active peptide-based compounds. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Role of the conformational versatility of the neurotrophin N-terminal regions in their recognition by Trk receptors
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