Biology subjects

Wingreen, N. S.

Publications and source records attributed to Wingreen, N. S..

3 recordsLinked to original sources

bioRxiv2018

Revealing evolutionary constraints on proteins through sequence analysis

Alignments of large numbers of protein sequences have revealed \"sectors\" of collectively coevolving amino acids in several protein families. Here, we show that selection acting on any relevant physical property of a protein, e.g. the elastic energy of an important conformational change, can give rise to such a sector. We demonstrate that the main signature of these physical sectors lies in the smalleigenvalue modes of the covariance matrix of the selected sequences. This simple, generic model leads us to propose a principled method to identify sectors, along with the magnitudes of mutational effects, from sequence data.

biophysics↗

bioRxiv2018

Regulation of T cell expansion by antigen presentation dynamics

An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher affinity clones can suppress the proliferation of lower affinity clones, thereby promoting the specificity of the response. Employing the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response.

immunology↗

bioRxiv2018

E. coli translation strategies differ across nutrient conditions

For cells to grow faster they must increase their protein production rate. Microorganisms have traditionally been thought to accomplish this increase by producing more ribosomes to enhance protein synthesis capacity, leading to the linear relationship between ribosome level and growth rate observed under most growth conditions previously examined. Past studies have suggested that this linear relationship represents an optimal resource allocation strategy for each growth rate, independent of any specific nutrient state. Here we investigate protein production strategies in continuous cultures limited for carbon, nitrogen, and phosphate, which differentially impact substrate supply for protein versus nucleic acid metabolism. Unexpectedly, we find that at slow growth rates, E. coli achieves the same protein production rate using three different strategies under the three different nutrient limitations. Upon phosphate (P) limitation, translation is slow due to a particularly low abundance of ribosomes, which are RNA-rich and thus particularly costly for phosphorous-limited cells. In nitrogen (N) limitation, translation is slowed by limited glutamine and stalling at glutamine codons, resulting is slow elongation. In carbon (C) limitation, translation is slowed by accumulation of inactive ribosomes not bound to mRNA. These extra ribosomes enable rapid growth acceleration upon nutrient upshift. Thus, bacteria tune ribosome usage across different limiting nutrients to enable balanced nutrient-limited growth while also preparing for future nutrient upshifts.

microbiology↗