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c-Abl Tyrosine Kinase Adopts Multiple Active Conformational States in Solution

Overview of attention for article published in Biochemistry (00062979), June 2016
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Title
c-Abl Tyrosine Kinase Adopts Multiple Active Conformational States in Solution
Published in
Biochemistry (00062979), June 2016
DOI 10.1021/acs.biochem.6b00202
Pubmed ID
Authors

John Badger, Prerna Grover, Haibin Shi, Shoghag B. Panjarian, John R. Engen, Thomas E. Smithgall, Lee Makowski

Abstract

Protein-tyrosine kinases of the Abl family have diverse roles in normal cellular regulation and drive several forms of leukemia as oncogenic fusion proteins. In the crystal structure of the c-Abl kinase core, the SH2 and SH3 domains dock onto the back of the kinase domain, resulting in a compact, assembled state. This inactive conformation is stabilized by the interaction of the myristoylated N-cap with a pocket in the C-lobe of the kinase domain. Mutations that perturb these intramolecular interactions result in kinase activation. Here we present X-ray scattering solution structures of multi-domain c-Abl kinase core proteins modeling diverse active states. Surprisingly, the relative positions of the regulatory Ncap, SH3 and SH2 domains in an active myristic acid binding pocket mutant (A356N) were virtually identical to those of the assembled wild-type kinase core, indicating that Abl kinase activation does not require dramatic reorganization of the downregulated core structure. In contrast, the positions of the SH2 and SH3 domains in a clinically relevant imatinib-resistant gatekeeper mutant (T315I) appear to be reconfigured relative to their positions in the wild-type protein. Our results demonstrate that c-Abl kinase activation can occur either with (T315I) or without (A356N) global allosteric changes in the core, revealing the potential for previously unrecognized signaling diversity.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 22 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 22 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 4 18%
Student > Bachelor 4 18%
Researcher 4 18%
Student > Doctoral Student 2 9%
Student > Master 2 9%
Other 3 14%
Unknown 3 14%
Readers by discipline Count As %
Chemistry 8 36%
Agricultural and Biological Sciences 5 23%
Biochemistry, Genetics and Molecular Biology 5 23%
Unknown 4 18%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 June 2016.
All research outputs
#7,689,658
of 12,307,279 outputs
Outputs from Biochemistry (00062979)
#16,780
of 19,077 outputs
Outputs of similar age
#149,832
of 275,497 outputs
Outputs of similar age from Biochemistry (00062979)
#113
of 188 outputs
Altmetric has tracked 12,307,279 research outputs across all sources so far. This one is in the 23rd percentile – i.e., 23% of other outputs scored the same or lower than it.
So far Altmetric has tracked 19,077 research outputs from this source. They receive a mean Attention Score of 3.8. This one is in the 7th percentile – i.e., 7% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 275,497 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 36th percentile – i.e., 36% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 188 others from the same source and published within six weeks on either side of this one. This one is in the 23rd percentile – i.e., 23% of its contemporaries scored the same or lower than it.