CDC42 binds PAK4 via an extended GTPase-effector interface

Ha, Byung Hak; Boggon, Titus J.

doi:10.1073/pnas.1717437115

Title: CDC42 binds PAK4 via an extended GTPase-effector interface

Journal Article · Tue Jan 02 00:00:00 EST 2018 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1717437115· OSTI ID:1432871

Ha, Byung Hak ^[1]; Boggon, Titus J. ^[2]

Yale Univ. School of Medicine, New Haven, CT (United States)
Yale Univ. School of Medicine, New Haven, CT (United States); Yale Univ., New Haven, CT (United States)

The p21-activated kinase (PAK) group of serine/threonine kinases are downstream effectors of RHO GTPases and play important roles in regulation of the actin cytoskeleton, cell growth, survival, polarity, and development. Here we probe the interaction of the type II PAK, PAK4, with RHO GTPases. Using solution scattering we find that the full-length PAK4 heterodimer with CDC42 adopts primarily a compact organization. Furthermore, X-ray crystallography reveals the molecular nature of the interaction between PAK4 and CDC42 and shows that in addition to the canonical PAK4 CDC42/RAC interactive binding (CRIB) domain binding to CDC42 there are unexpected contacts involving the PAK4 kinase C-lobe, CDC42, and the PAK4 polybasic region. These additional interactions modulate kinase activity and increase the binding affinity of CDC42 for full-length PAK4 compared with the CRIB domain alone. We therefore show that the interaction of CDC42 with PAK4 can influence kinase activity in a previously unappreciated manner.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Institute of General Medical Sciences; USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: GM103403; RR029205; P41 GM111244; KP1605010; S10 OD012331; SC0012704; R01GM102262; S10OD018007

OSTI ID:: 1432871

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, Issue 3; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 26 works

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The subcellular localization of type I p21-activated kinases is controlled by the disordered variable region and polybasic sequences Sun, Xiaowen; Su, Valerie L.; Calderwood, David A. Journal of Biological Chemistry, Vol. 294, Issue 39 https://doi.org/10.1074/jbc.ra119.007692	journal	August 2019
PAK4 signaling in health and disease: defining the PAK4–CREB axis Won, So-Yoon; Park, Jung-Jin; Shin, Eun-Young Experimental & Molecular Medicine, Vol. 51, Issue 2 https://doi.org/10.1038/s12276-018-0204-0	journal	February 2019
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