Campus Units

Biochemistry, Biophysics and Molecular Biology, Roy J. Carver Department of

Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

10-23-2014

Journal or Book Title

Journal of Molecular Biology

Volume

426

Issue

21

First Page

3656

Last Page

3669

DOI

10.1016/j.jmb.2014.08.018

Abstract

Despite high homology among non-receptor tyrosine kinases, different kinase families employ a diverse array of regulatory mechanisms. For example, the catalytic kinase domains of the Tec family kinases are inactive without assembly of the adjacent regulatory domains, whereas the Src kinase domains are autoinhibited by the assembly of similar adjacent regulatory domains. Using molecular dynamic simulations, biochemical assays, and biophysical approaches, we have uncovered an isoleucine residue in the kinase domain of the Tec family member Btk that, when mutated to the closely related leucine, leads to a shift in the conformational equilibrium of the kinase domain toward the active state. The single amino acid mutation results in measureable catalytic activity for the Btk kinase domain in the absence of the regulatory domains. We suggest this isoleucine side chain in the Tec family kinases acts as a ‘wedge’ that restricts the conformational space available to key regions in the kinase domain, preventing activation until the kinase domain associates with its regulatory subunits and overcomes the energetic barrier to activation imposed by the isoleucine side chain.

Comments

This is a manuscript of an article published as Boyken, Scott E., Nikita Chopra, Qian Xie, Raji E. Joseph, Thomas E. Wales, D. Bruce Fulton, John R. Engen, Robert L. Jernigan, and Amy H. Andreotti. "A conserved isoleucine maintains the inactive state of Bruton's tyrosine kinase." Journal of molecular biology 426, no. 21 (2014): 3656-3669. doi: 10.1016/j.jmb.2014.08.018. Posted with permission.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Copyright Owner

Elsevier Ltd

Language

en

File Format

application/pdf

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