Leucine-rich hydrophobic clusters promote folding of the N-terminus of the intrinsically disordered transactivation domain of p53

Espinoza-Fonseca, L. Michel

doi:10.1016/j.febslet.2008.12.060

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Volume 583, Issue 3 , Pages 556-560, 4 February 2009

Leucine-rich hydrophobic clusters promote folding of the N-terminus of the intrinsically disordered transactivation domain of p53

Edited by Paul Bertone

Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA

Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala, Mexico City 11340, Mexico

Received 3 September 2008; received in revised form 8 December 2008; accepted 24 December 2008. published online 19 January 2009.

Abstract

Molecular dynamics simulations have been performed on the intrinsically disordered 39-residue N-terminal transactivation domain of p53 (p53_1-39). Simulations not only revealed that p53_1-39 is natively compact, but also possesses a folded structure. Furthermore, leucine-rich hydrophobic clusters were found to play a crucial role in the formation and stabilization of the folded structure of p53_1-39. Collapsing in the sub-microsecond timescale might allow for rapid conformational turnovers of p53_1-39, necessary for its efficient transactivation activity and modulation. Fast collapsing might be the result of unique conformational landscapes, featuring several energy minima separated by small energy barriers. It is suggested that IDPs with highly specialized functions in the cell, such as transactivation, possibly display more ordered patterns than their less specialized counterparts.

Keywords: Intrinsically disordered protein, p53 transactivation domain, Protein folding, Molecular dynamics simulation, Leucine-rich hydrophobic cluster