CDC42 binds PAK4 via an extended GTPase-effector interface
Abstract
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.
- Authors:
-
- 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)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- 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)
- OSTI Identifier:
- 1432871
- Grant/Contract Number:
- GM103403; RR029205; P41 GM111244; KP1605010; S10 OD012331; SC0012704; R01GM102262; S10OD018007
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 115; Journal Issue: 3; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; small GTPase; protein kinase; protein–protein interaction; signal transduction; crystal structure
Citation Formats
Ha, Byung Hak, and Boggon, Titus J. CDC42 binds PAK4 via an extended GTPase-effector interface. United States: N. p., 2018.
Web. doi:10.1073/pnas.1717437115.
Ha, Byung Hak, & Boggon, Titus J. CDC42 binds PAK4 via an extended GTPase-effector interface. United States. https://doi.org/10.1073/pnas.1717437115
Ha, Byung Hak, and Boggon, Titus J. Tue .
"CDC42 binds PAK4 via an extended GTPase-effector interface". United States. https://doi.org/10.1073/pnas.1717437115. https://www.osti.gov/servlets/purl/1432871.
@article{osti_1432871,
title = {CDC42 binds PAK4 via an extended GTPase-effector interface},
author = {Ha, Byung Hak and Boggon, Titus J.},
abstractNote = {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.},
doi = {10.1073/pnas.1717437115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 3,
volume = 115,
place = {United States},
year = {Tue Jan 02 00:00:00 EST 2018},
month = {Tue Jan 02 00:00:00 EST 2018}
}
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