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Solution structures and biophysical analysis of full-length group A PAKs reveal they are monomeric and auto-inhibited in cis

DOI: 10.1042/BCJ20180867 DOI Help

Authors: Fiona J. Sorrell (Structural Genomics Consortium, University of Oxford) , Lena M. Kilian (Structural Genomics Consortium, University of Oxford) , Jonathan M. Elkins (Structural Genomics Consortium, University of Oxford; Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical Journal , VOL 476 , PAGES 1037 - 1051

State: Published (Approved)
Published: April 2019

Open Access Open Access

Abstract: 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 blocking the binding of substrates, and CDC42 or Rac binding to the regulatory domain relieves this auto-inhibition allowing auto-phosphorylation on the kinase domain 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 to previous assumptions, group A PAKs are monomeric both before and after activation, consistent with an activation mechanism of cis -autoinhibition and initial cis -autophosphorylation, followed by transient dimerization to allow trans- autophosphorylation for full activation, yielding a monomeric active PAK protein.

Subject Areas: Biology and Bio-materials


Beamlines: B21-High Throughput SAXS , I03-Macromolecular Crystallography

Documents:
BCJ20180867.full.pdf