Posted by: Dan | June 18, 2007

Kinase Structures and Autoinhibition

As more structures are being solved for multimodular signaling proteins, the regulatory kinetics (on, off, and everything in between) is coming into greater clarity. For instance, the recently solved structural basis for allosteric autoinhibition of focal adhesion kinase (FAK), along with the ZAP-70 tyrosine kinase, and the protypical tyrosine kinase Src.

As with all comparisons within protein families involving crystallography, the stories that come out of the research relate to the structural plasticity of the crystals themselves, and how homologous proteins (of both orthologous and paralogous flavors) find such diverse regulatory mechanisms. For kinases in general, we have the basic catalytic unit, which evolved long before the advent of eukaryotic cells, and diverged into tyrosine, serine/threonine, lipid, and atypical phosphorylating enzymes by many gene duplication and exaption events.

For individual kinase subfamilies, innovative mechanisms for modulating catalytic activity abound. Every part of a protein not absolutely required (or conserved) for catalytic activity becomes a candidate enhancing mutation, enabling both complexity and control.

There is now a growing list of kinase families in which autoinhibition has been characterized structurally. In addition to the Src, Abl, ZAP-70, and FAK families of cytoplasmic protein tyrosine kinases, autoinhibition has also been structurally demonstrated in the AGC serine/threonine kinase family (for example, PKA), the receptor tyrosine kinase family, and the calcium/calmodulin-dependent protein kinase (CaMK) family. All three kinase families mediate inhibition in unique ways, from a pseudosubstrate sequence in the case of PKA (Kim et al., 2005) to a juxtamembrane segment in the receptor tyrosine kinases that occupies the catalytic cleft (Wybenga-Groot et al., 2001) to a C-terminal autoinhibitory helix-loop-helix segment in the case of CaMKI (Goldberg et al., 1996). How many unique mechanisms of kinase autoinhibition are there? A quick glance at the human protein kinase family tree should leave kinase family dramatists feeling reassured that they are unlikely to run out of material any time soon.

In the case of the newly solved structural basis of FAK autoinhibition, Lietha et al. (2007) elaborate on the critical conformational mechanisms of protein behavior. They show how distinct binding surfaces achieve inhibition by blocking access to the active site. The FERM domain docks onto the kinase domain, covering the substrate-binding site, and Lietha et al. convincingly demonstrate that activation of FAK involves a sequential displacement of the FERM domain from the kinase and concomitant tyrosine phosphorylation of the activation loop.

I know, I’ve probably lost everyone’s attention by now, which is unfortunate, because it is this level of detail that we have supporting evolution (diversification, multimodular regulation, and other things too complex for the layperson to keep up with) at the smallest building blocks.

In the case of FAK, however, I’d like to make one additional note. The autoinhibitory mechanism by the N-terminal FERM domain was first identified by my former labmate, Lee Ann (Cooper) Cohen (Cooper, Shen and Guan, 2003). I recall distinctly how that experiment was highly speculative, simply guessing that transfecting the N-terminal region (which looked awfully like a FERM domain) might possibly inhibit endogenous FAK. It turned out she was right.

More can be heard on the evolution of allosteric autoinhibition on the last 8 minutes of this week’s Cell podcast (.mp3)

  • Leonard TA, Hurley JH. Two Kinase Family Dramas. Cell 15 June 2007, 129(6): 1037-1038.
  • Lietha D, Cai X, Ceccarelli DFJ, Li Y, Schaller MD, Eck MJ. Structural Basis for the Autoinhibition of Focal Adhesion Kinase. Cell 15 June 2007, 129(6): 1177-1187.
  • Cooper LA, Shen TL, Guan JL. Regulation of focal adhesion kinase by its amino-terminal domain through an autoinhibitory interaction. Mol Cell Biol. 2003 Nov, 23(22): 8030-41.

Responses

  1. […] century seems to be fixated on the workings of the smallest molecules at this fine scale, including Kinase Structures and Autoinhibition. As more structures are being solved for multimodular signaling proteins, the regulatory kinetics […]

  2. […] 20th, 2007 by Dan In the same vein as my recent post on kinase structures and autoinhibition of multimodular signaling proteins, last week’s Nature had a post on Rewiring cellular […]

  3. […] Kinase Structures and Autoinhibition […]


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