Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate. Ha, B. H., Davis, M. J, Chen, C., Lou, H. J., Gao, J., Zhang, R., Krauthammer, M., Halaban, R., Schlessinger, J., Turk, B. E, & Boggon, T. J Proceedings of the National Academy of Sciences of the United States of America, 109(40):16107–16112, oct, 2012.
doi  abstract   bibtex   
The type II p21-activated kinases (PAKs) are key effectors of RHO-family GTPases involved in cell motility, survival, and proliferation. Using a structure-guided approach, we discovered that type II PAKs are regulated by an N-terminal autoinhibitory pseudosubstrate motif centered on a critical proline residue, and that this regulation occurs independently of activation loop phosphorylation. We determined six X-ray crystal structures of either full-length PAK4 or its catalytic domain, that demonstrate the molecular basis for pseudosubstrate binding to the active state with phosphorylated activation loop. We show that full-length PAK4 is constitutively autoinhibited, but mutation of the pseudosubstrate releases this inhibition and causes increased phosphorylation of the apoptotic regulation protein Bcl-2/Bcl-X(L) antagonist causing cell death and cellular morphological changes. We also find that PAK6 is regulated by the pseudosubstrate region, indicating a common type II PAK autoregulatory mechanism. Finally, we find Src SH3, but not beta-PIX SH3, can activate PAK4. We provide a unique understanding for type II PAK regulation.
@article{Ha2012,
abstract = {The type II p21-activated kinases (PAKs) are key effectors of RHO-family GTPases  involved in cell motility, survival, and proliferation. Using a structure-guided approach, we discovered that type II PAKs are regulated by an N-terminal autoinhibitory pseudosubstrate motif centered on a critical proline residue, and that this regulation occurs independently of activation loop phosphorylation. We determined six X-ray crystal structures of either full-length PAK4 or its catalytic domain, that demonstrate the molecular basis for pseudosubstrate binding to the active state with phosphorylated activation loop. We show that full-length PAK4 is constitutively autoinhibited, but mutation of the pseudosubstrate releases this inhibition and causes increased phosphorylation of the apoptotic regulation protein Bcl-2/Bcl-X(L) antagonist causing cell death and cellular morphological changes. We also find that PAK6 is regulated by the pseudosubstrate region, indicating a common type II PAK autoregulatory mechanism. Finally, we find Src SH3, but not beta-PIX SH3, can activate PAK4. We provide a unique understanding for type II PAK regulation.},
author = {Ha, Byung Hak and Davis, Matthew J and Chen, Catherine and Lou, Hua Jane and Gao, Jia and Zhang, Rong and Krauthammer, Michael and Halaban, Ruth and Schlessinger, Joseph and Turk, Benjamin E and Boggon, Titus J},
doi = {10.1073/pnas.1214447109},
issn = {1091-6490 (Electronic)},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {Amino Acid Sequence,Base Sequence,Catalytic Domain,Crystallography, X-Ray,Homeostasis,Humans,Models, Molecular,Molecular Sequence Data,Nerve Tissue Proteins,Phosphorylation,Sequence Analysis, DNA,Signal Transduction,bcl-Associated Death Protein,genetics,metabolism,p21-Activated Kinases,physiology},
language = {eng},
month = {oct},
number = {40},
pages = {16107--16112},
pmid = {22988085},
title = {{Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate.}},
volume = {109},
year = {2012}
}

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