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Casitas B-lineage lymphoma linker helix mutations found in myeloproliferative neoplasms affect conformation

Overview of attention for article published in BMC Biology, September 2016
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Title
Casitas B-lineage lymphoma linker helix mutations found in myeloproliferative neoplasms affect conformation
Published in
BMC Biology, September 2016
DOI 10.1186/s12915-016-0298-6
Pubmed ID
Authors

Lori Buetow, Giancarlo Tria, Syed Feroj Ahmed, Andreas Hock, Hao Dou, Gary J. Sibbet, Dmitri I. Svergun, Danny T. Huang

Abstract

Casitas B-lineage lymphoma (Cbl or c-Cbl) is a RING ubiquitin ligase that negatively regulates protein tyrosine kinase (PTK) signalling. Phosphorylation of a conserved residue (Tyr371) on the linker helix region (LHR) between the substrate-binding and RING domains is required to ubiquitinate PTKs, thereby flagging them for degradation. This conserved Tyr is a mutational hotspot in myeloproliferative neoplasms. Previous studies have revealed that select point mutations in Tyr371 can potentiate transformation in cells and mice but not all possible mutations do so. To trigger oncogenic potential, Cbl Tyr371 mutants must perturb the LHR-substrate-binding domain interaction and eliminate PTK ubiquitination. Although structures of native and pTyr371-Cbl are available, they do not reveal how Tyr371 mutations affect Cbl's conformation. Here, we investigate how Tyr371 mutations affect Cbl's conformation in solution and how this relates to Cbl's ability to potentiate transformation in cells. To explore how Tyr371 mutations affect Cbl's properties, we used surface plasmon resonance to measure Cbl mutant binding affinities for E2 conjugated with ubiquitin (E2-Ub), small angle X-ray scattering studies to investigate Cbl mutant conformation in solution and focus formation assays to assay Cbl mutant transformation potential in cells. Cbl Tyr371 mutants enhance E2-Ub binding and cause Cbl to adopt extended conformations in solution. LHR flexibility, RING domain accessibility and transformation potential are associated with the extent of LHR-substrate-binding domain perturbation affected by the chemical nature of the mutation. More disruptive mutants like Cbl Y371D or Y371S are more extended and the RING domain is more accessible, whereas Cbl Y371F mimics native Cbl in solution. Correspondingly, the only Tyr371 mutants that potentiate transformation in cells are those that perturb the LHR-substrate-binding domain interaction. c-Cbl's LHR mutations are only oncogenic when they disrupt the native state and fail to ubiquitinate PTKs. These findings provide new insights into how LHR mutations deregulate c-Cbl.

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Mendeley readers

The data shown below were compiled from readership statistics for 20 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 20 100%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 6 30%
Researcher 3 15%
Student > Ph. D. Student 3 15%
Student > Master 2 10%
Other 1 5%
Other 2 10%
Unknown 3 15%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 5 25%
Medicine and Dentistry 5 25%
Agricultural and Biological Sciences 4 20%
Computer Science 1 5%
Immunology and Microbiology 1 5%
Other 1 5%
Unknown 3 15%

Attention Score in Context

This research output has an Altmetric Attention Score of 2. 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 27 October 2017.
All research outputs
#9,343,695
of 15,918,909 outputs
Outputs from BMC Biology
#1,122
of 1,363 outputs
Outputs of similar age
#131,399
of 267,850 outputs
Outputs of similar age from BMC Biology
#1
of 1 outputs
Altmetric has tracked 15,918,909 research outputs across all sources so far. This one is in the 39th percentile – i.e., 39% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,363 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 19.6. This one is in the 14th percentile – i.e., 14% of its peers scored the same or lower than it.
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