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Thermodynamic and Phylogenetic Insights into hnRNP A1 Recognition of the HIV‑1 Exon Splicing Silencer 3 Element

Overview of attention for article published in Biochemistry, March 2014
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Title
Thermodynamic and Phylogenetic Insights into hnRNP A1 Recognition of the HIV‑1 Exon Splicing Silencer 3 Element
Published in
Biochemistry, March 2014
DOI 10.1021/bi500180p
Pubmed ID
Authors

Carrie Rollins, Jeffrey D. Levengood, Brittany D. Rife, Marco Salemi, Blanton S. Tolbert

Abstract

Complete expression of the HIV-1 genome requires balanced usage of suboptimal splice sites. The 3' acceptor site A7 (ssA7) is negatively regulated in part by an interaction between the host hnRNP A1 protein and a viral splicing silencer (ESS3). Binding of hnRNP A1 to ESS3 and other upstream silencers is sufficient to occlude spliceosome assembly. Efforts to understand the splicing repressive properties of hnRNP A1 on ssA7 have revealed hnRNP A1 binds specific sites within the context of a highly folded RNA structure; however, biochemical models assert hnRNP A1 disrupts RNA structure through cooperative spreading. In an effort to improve our understanding of the ssA7 binding properties of hnRNP A1, herein we have performed a combined phylogenetic and biophysical study of the interaction of its UP1 domain with ESS3. Phylogenetic analyses of group M sequences (x̅ = 2860) taken from the Los Alamos HIV database reveal the ESS3 stem loop (SL3(ESS3)) structure has been conserved throughout HIV-1 evolution, despite variations in primary sequence. Calorimetric titrations with UP1 clearly show the SL3(ESS3) structure is a critical binding determinant because deletion of the base-paired region reduces the affinity by ∼150-fold (Kd values of 27.8 nM and 4.2 μM). Cytosine substitutions of conserved apical loop nucleobases show UP1 preferentially binds purines over pyrimidines, where site-specific interactions were detected via saturation transfer difference nuclear magnetic resonance. Chemical shift mapping of the UP1-SL3(ESS3) interface by (1)H-(15)N heteronuclear single-quantum coherence spectroscopy titrations reveals a broad interaction surface on UP1 that encompasses both RRM domains and the inter-RRM linker. Collectively, our results describe a UP1 binding mechanism that is likely different from current models used to explain the alternative splicing properties of hnRNP A1.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 27 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 1 4%
Unknown 26 96%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 7 26%
Researcher 5 19%
Professor 4 15%
Professor > Associate Professor 2 7%
Student > Bachelor 1 4%
Other 1 4%
Unknown 7 26%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 7 26%
Agricultural and Biological Sciences 6 22%
Chemistry 4 15%
Immunology and Microbiology 1 4%
Medicine and Dentistry 1 4%
Other 1 4%
Unknown 7 26%
Attention Score in Context

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 20 March 2014.
All research outputs
#21,866,582
of 24,397,600 outputs
Outputs from Biochemistry
#21,462
of 22,293 outputs
Outputs of similar age
#199,439
of 229,249 outputs
Outputs of similar age from Biochemistry
#85
of 91 outputs
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