ABSTRACT
There is interest in admission criteria that predict future success in biomedical graduate school programs, but identifying predictors of PhD attainment is inherently complex. In particular, high noncompletion rates of PhD programs have long been recognized as a major crisis. Here, we present a quantitative analysis of the PhD students enrolled in the Department of Biochemistry and Biophysics at Texas A&M University between 1980 and 2010. The input variables included sex, country of citizenship, undergraduate grade point average (GPA), and Graduate Record Examination (GRE) scores (Verbal and Quantitative Reasoning). Only GPA was a significant predictor of PhD completion based on logistic regression. We also examined associations involving nonbinary measures of success (PhD duration, first author, and total number of publications) among students who completed a PhD. GPA was again associated with the PhD duration. No enrollment variable was strongly associated with publication output. Despite potential limitations, this analysis is the first to suggest an undergraduate GPA association with PhD completion in life sciences. These results from a large state university in a predominantly rural area expand the range of programs from which such analyses have been reported.
Subject(s)
School Admission Criteria , Students , Biochemistry , Educational Measurement , Humans , SchoolsABSTRACT
The 1918 influenza A virus (IAV) caused the worst flu pandemic in human history. Non-structural protein 1 (NS1) is an important virulence factor of the 1918 IAV and antagonizes host antiviral immune responses. NS1 increases virulence by activating phosphoinositide 3-kinase (PI3K) via binding to the p85ß subunit of PI3K. Intriguingly, unlike the NS1 of other human IAV strains, 1918 NS1 hijacks another host protein, CRK, to form a ternary complex with p85ß, resulting in hyperactivation of PI3K. However, the molecular basis of the ternary interaction between 1918 NS1, CRK, and PI3K remains elusive. Here, we report the structural and thermodynamic bases of the ternary interaction. We find that the C-terminal tail (CTT) of 1918 NS1 remains highly flexible in the complex with p85ß. Thus, the CTT of 1918 NS1 in the complex with PI3K can efficiently hijack CRK. Notably, our study indicates that 1918 NS1 enhances its affinity to p85ß in the presence of CRK, which might result in enhanced activation of PI3K. Our results provide structural insight into how 1918 NS1 hijacks two host proteins simultaneously.
Subject(s)
Influenza A virus , Influenza, Human/metabolism , Influenza, Human/virology , Phosphatidylinositol 3-Kinases/chemistry , Proto-Oncogene Proteins c-crk/chemistry , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Animals , History, 20th Century , Humans , Influenza, Human/history , Models, Biological , Models, Molecular , Multiprotein Complexes , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , Proto-Oncogene Proteins c-crk/metabolism , Structure-Activity RelationshipABSTRACT
The 1918 influenza A virus (IAV) caused the most severe flu pandemic in recorded human history. Nonstructural protein 1 (NS1) is an important virulence factor of the 1918 IAV. NS1 antagonizes host defense mechanisms through interactions with multiple host factors. One pathway by which NS1 increases virulence is through the activation of phosphoinositide 3-kinase (PI3K) by binding to its p85ß subunit. Here we present the mechanism underlying the molecular recognition of the p85ß subunit by 1918 NS1. Using X-ray crystallography, we determine the structure of 1918 NS1 complexed with p85ß of human PI3K. We find that the 1918 NS1 effector domain (1918 NS1ED) undergoes a conformational change to bind p85ß. Using NMR relaxation dispersion and molecular dynamics simulation, we identify that free 1918 NS1ED exists in a dynamic equilibrium between p85ß-binding-competent and -incompetent conformations in the submillisecond timescale. Moreover, we discover that NS1ED proteins of 1918 (H1N1) and Udorn (H3N2) strains exhibit drastically different conformational dynamics and binding kinetics to p85ß. These results provide evidence of strain-dependent conformational dynamics of NS1. Using kinetic modeling based on the experimental data, we demonstrate that 1918 NS1ED can result in the faster hijacking of p85ß compared to Ud NS1ED, although the former has a lower affinity to p85ß than the latter. Our results suggest that the difference in binding kinetics may impact the competition with cellular antiviral responses for the activation of PI3K. We anticipate that our findings will increase the understanding of the strain-dependent behaviors of influenza NS1 proteins.
