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The group A p21-activated kinases (PAKs) exist in an auto-inhibited form until activated by GTPase binding and auto-phosphorylation. In the auto-inhibited form, a regulatory domain binds to the kinase domain (KD) blocking the binding of substrates, and CDC42 or Rac binding to the regulatory domain relieves this auto-inhibition allowing auto-phosphorylation on the KD activation loop. We have determined the crystal structure of the PAK3 catalytic domain and by small angle X-ray scattering, the solution-phase structures of full-length inactive PAK1 and PAK3. The structures reveal a compact but elongated molecular shape that demonstrates that, together with multiple independent biophysical measurements and in contrast with previous assumptions, group A PAKs are monomeric both before and after activation, consistent with an activation mechanism of cis-auto-inhibition and initial cis-auto-phosphorylation, followed by transient dimerisation to allow trans-auto-phosphorylation for full activation, yielding a monomeric active PAK protein.

Original publication




Journal article


Biochem J

Publication Date





1037 - 1051


SAXS, kinase, structure, Binding Sites, Biophysical Phenomena, Catalytic Domain, Crystallography, X-Ray, Enzyme Activation, Humans, Kinetics, Models, Molecular, Phosphorylation, Protein Conformation, Recombinant Proteins, Scattering, Small Angle, Solutions, X-Ray Diffraction, cdc42 GTP-Binding Protein, p21-Activated Kinases