6FD3

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

(2019) Biochem J 476: 1037-1051

• PubMed: 30858169 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1042/BCJ20180867
• Primary Citation of Related Structures:  
  6FD3


• PubMed 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 (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.

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Organizational Affiliation: 

Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.