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Atomic view of the energy landscape in the allosteric regulation of Abl kinase

Nature Structural & Molecular Biology volume 24, pages 893–901 (2017)Cite this article

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Abstract

The activity of protein kinases is often regulated in an intramolecular fashion by signaling domains, which feature several phosphorylation or protein-docking sites. How kinases integrate such distinct binding and signaling events to regulate their activities is unclear, especially in quantitative terms. We used NMR spectroscopy to show how structural elements within the Abl regulatory module (RM) synergistically generate a multilayered allosteric mechanism that enables Abl kinase to function as a finely tuned switch. We dissected the structure and energetics of the regulatory mechanism to precisely measure the effects of various activating or inhibiting stimuli on Abl kinase activity. The data provide a mechanistic basis explaining genetic observations and reveal a previously unknown activator region within Abl. Our findings show that drug-resistance mutations in the Abl RM exert their allosteric effect by promoting the activated state of Abl and not by decreasing the drug affinity for the kinase.

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Figure 1: Structures of Abl.
Figure 2: Structure analysis of the Abl RM activating and inhibiting states.
Figure 3: Populations and energetics of Abl RM inhibiting and activating states.
Figure 4: Populations of Abl assembled and extended states.
Figure 5: Mechanistic basis for imatinib resistance of RM mutations.
Figure 6: Energy landscape of Abl allosteric regulation.

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Acknowledgements

The work was supported by National Institutes of Health grant GM122462 to C.G.K.

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Author notes

  1. Tamjeed Saleh and Paolo Rossi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Tamjeed Saleh, Paolo Rossi & Charalampos G Kalodimos

  2. Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, Minnesota, USA

    Tamjeed Saleh, Paolo Rossi & Charalampos G Kalodimos

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Contributions

T.S., P.R. and C.G.K. designed the study. T.S. performed all biochemical experiments. T.S. and P.R. recorded and analyzed the NMR data. P.R. determined the NMR structures. All authors contributed to and approved the manuscript.

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Correspondence to Charalampos G Kalodimos.

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Integrated supplementary information

Supplementary Figure 1 NMR characterization of Abl.

(a) Domain organization and primary sequence of the first N-terminal 557 residues of Abl (isoform 1b). (b) 1H-15N HSQC spectra of select Abl RM variants. (c) 1H-15N HSQC spectrum of U-2H,15N labeled AblΔcap (left) and 1H-13C HMQC spectra of U-2H, Met-13CH3, Ile-δ1-13CH3, Leu,Val-13CH3/13CH3 labeled Abl (right).

Supplementary Figure 2 Structure analysis of the Abl assembled and extended states versus the RM activating and inhibiting states.

(a-c)The assembled state of Abl (panel a) is shown superimposed onto the inhibiting state (panel b) and onto the activating state (panel c) of the isolated Abl RM. The KD is shown as a solvent-accessible surface and the RM in ribbon. The inhibiting and activating states are colored blue and yellow, respectively. In both states the connectorSH3/2 is colored orange and the linkerSH2-KD is colored red. The inhibiting state of the isolated Abl RM superimposes very well onto the RM of the assembled structure of Abl but the activating state does not and thus is not compatible with the assembled form of Abl. (d-f) The extended state of Abl (panel d) is shown superimposed onto the inhibiting state (panel F) and onto the activating state (panel F) of the isolated Abl RM. The inhibiting state of the RM is not compatible with the extended form of Abl with the linkerSH2-KD being too short to accommodate it (e.g. Asp252 in the inhibiting state is 40 Å away from the position of this residue in the extended form of Abl). In contrast, the activating state of RM is compatible with the extended form of Abl. (g) Modeling of the extended state in Ablmyr. The black sphere denotes the extreme N-terminal Gly2 residue that is myristoylated. The structural model shows that the cap is long enough to accommodate the activating state of Abl RM on top of the N-lobe (extended state) without the need for the myristoyl to be removed from the C-lobe pocket. (h,i) Three important Tyr residues that are phosphorylated by other kinases are shown in the assembled form (panel h), wherein they are buried at the domain interfaces, and in the extended form (panel i), wherein they are all exposed and thus accessible for phosphorylation.

Supplementary Figure 3 A two-state cooperative transition between the activating and inhibiting states.

(a) Probing the assembled (inhibited) state population in Abl using the NMR resonance of Met515. This residue is located in the C lobe, at the interface with the SH2 domain, and thus it has a different chemical shift in the assembled state than in the extended state. The chemical shift change of Met515 mirrors the change experienced by Met263 (Fig. 4a). (b) Methyl NOESY data show a strong NOE between Ile164 (SH2) and Met263 (N-lobe) in AblT231R indicating that the protein adopts the extended state in solution, in agreement with the crystal data (PDB ID 4XEY). (c) Plot of the population of the Abl RM activating state in several Abl variants measured by the chemical shift change of Lys143 (Fig. 3) and of the extended state of Abl measured by the chemical shift change of Met263 (Fig. 4). The data show a strong linear relationship with a slope of 1, indicating that all of the RM molecules in the activating state form the assembled Abl state. (d) Schematic of the interconversion between the inhibiting and activating states with two residues (Asn72 and Ala75) located in capC and two residues (Tyr245 and Gly246) located in the linkerSH2-KD marked. The spectra of the four residues are shown in panels E and F. (e,f) Superimposed 1H-15N spectra of three Abl RM variants: wild type (dark blue), Abl RMP242E P249E (magenta), Abl RMΔcapPxxP (green), and Abl RMT243P (blue). The spectra of Tyr245 and Gly246 are shown in panel E and the spectra of Asn72 and Ala75 are shown in panel F. The NMR data demonstrate that residues in different regions of Abl RM all exhibit a two-state transition between the activating and inhibiting states. The effect on the population of the two states by mutations in any region of Abl RM (e.g. P242E P249E in the linkerSH2-KD) is reflected in all other regions (e.g. capC). This indicates a two-state cooperative transition of the entire Abl RM.

Supplementary Figure 4 Solution structure of RM.

Ensemble of the 20 lowest energy structures of (a) inhibiting and (b) activating states

Supplementary Figure 5 The unstructured region of Abl RM, investigated by NMR.

(a) Plot of R2/R1 ratio. 15N relaxation rates of Abl RM backbone as a function of residue number. The R2/R1 informs on the tumbling of the molecule, lower values indicate higher tumbling. (b) Secondary structure populations of Abl RM were obtained using the δ2D algorithm.

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Supplementary Data Sets 1 and 2

Uncropped gels and standard deviation (SD) for the measured kinase activities from triplicate experiments (PDF 9884 kb)

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Saleh, T., Rossi, P. & Kalodimos, C. Atomic view of the energy landscape in the allosteric regulation of Abl kinase. Nat Struct Mol Biol 24, 893–901 (2017). https://doi.org/10.1038/nsmb.3470

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