Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.bbrc.2013.07.047
Title: NMR binding and crystal structure reveal that intrinsically-unstructured regulatory domain auto-inhibits PAK4 by a mechanism different from that of PAK1
Authors: Wang, W.
Lim, L. 
Baskaran, Y.
Manser, E.
Song, J. 
Keywords: Auto-inhibition
Intrinsically unstructured protein (IUP)
Isothermal titration calorimetry (ITC)
NMR spectroscopy
P21-activated kinases (PAKs)
X-ray crystallography
Issue Date: 16-Aug-2013
Citation: Wang, W., Lim, L., Baskaran, Y., Manser, E., Song, J. (2013-08-16). NMR binding and crystal structure reveal that intrinsically-unstructured regulatory domain auto-inhibits PAK4 by a mechanism different from that of PAK1. Biochemical and Biophysical Research Communications 438 (1) : 169-174. ScholarBank@NUS Repository. https://doi.org/10.1016/j.bbrc.2013.07.047
Abstract: Six human PAK members are classified into groups I (PAKs 1-3) and II (PAK4-6). Previously, only group I PAKs were thought to be auto-inhibited but very recently PAK4, the prototype of group II PAKs, has also been shown to be auto-inhibited by its N-terminal regulatory domain. However, the complete auto-inhibitory domain (AID) sequence remains undefined and the mechanism underlying its auto-inhibition is largely elusive. Here, the N-terminal regulatory domain of PAK4 sufficient for auto-inhibiting and binding Cdc42/Rac was characterized to be intrinsically unstructured, but nevertheless we identified the entire AID sequence by NMR. Strikingly, an AID peptide was derived by deleting the binding-unnecessary residues, which has a Kd of 320. nM to the PAK4 catalytic domain. Consequently, the PAK4 crystal structure complexed with the entire AID has been determined, which reveals that the complete kinase cleft is occupied by 20 AID residuescomposed of an N-terminal α-helix and a previously-identified pseudosubstrate motif, thus achieving auto-inhibition. Our study reveals that PAK4 is auto-inhibited by a novel mechanism which is completely different from that for PAK1, thus bearing critical implications for design of inhibitors specific for group II PAKs. © 2013 Elsevier Inc.
Source Title: Biochemical and Biophysical Research Communications
URI: http://scholarbank.nus.edu.sg/handle/10635/101228
ISSN: 0006291X
DOI: 10.1016/j.bbrc.2013.07.047
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