Structural dynamics is a determinant of the functional significance of missense variants
Accurate evaluation of the effect of point mutations on protein function is essential to assessing the genesis and prognosis of many inherited diseases and cancer types. Currently, a wealth of computational tools has been developed for pathogenicity prediction. Two major types of data are used to this aim: sequence conservation/evolution and structural properties. Here, we demonstrate in a systematic way that another determinant of the functional impact of missense variants is the protein’s structural dynamics. Measurable improvement is shown in pathogenicity prediction by taking into consideration the dynamical context and implications of the mutation. Our study suggests that the class of dynamics descriptors introduced here may be used in conjunction with existing features to not only increase the prediction accuracy of the impact of variants on biological function, but also gain insight into the physical basis of the effect of missense variants.
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Graduate student and Bahar lab member She Zhang will be representing Pitt graduate students at Pitt Day in Harrisburg on March 20th. Pitt Day is an annual gathering to highlight the accomplishments and challenges of the Pitt community and to help inform elected officials of the positive impact that Pitt has on the commonwealth.
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“Protein Actions” book by Bahar, Jernigan and Dill, was selected amongst the APA Prose award 2018 winners in the category of Textbook/Biological and Life Sciences, by the Professional and Scholarly Publishing Division of the Association of American Publishers (see https://proseawards.com/winners/)
The PROSE Awards annually recognize the very best in professional and scholarly publishing by bringing attention to distinguished books, journals, and electronic content in 58 categories (see https://proseawards.com/) .
Dr. Lansing Taylor, Distinguished Professor and Allegheny Foundation Professor of Computational & Systems Biology and Director of the University of Pittsburgh Drug Discovery Institute, was featured in Pittsburgh Business Times discussing his life and work.
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Heterogeneities in Axonal Structure and Transporter Distribution Lower Dopamine Reuptake Efficiency
Efficient clearance of dopamine (DA) from the synapse is key to regulating dopaminergic signaling. This role is fulfilled by DA transporters (DATs). Recent advances in the structural characterization of DAT from Drosophila (dDAT) and in high-resolution imaging of DA neurons and the distribution of DATs in living cells now permit us to gain a mechanistic understanding of DA reuptake events in silico. Using electron microscopy images and immunofluorescence of transgenic knock-in mouse brains that express hemagglutinin-tagged DAT in DA neurons, we reconstructed a realistic environment for MCell simulations of DA reuptake, wherein the identity, population and kinetics of homology-modeled human DAT (hDAT) sub-states were derived from molecular simulations. The complex morphology of axon terminals near active zones was observed to give rise to large variations in DA reuptake efficiency, and thereby in extracellular DA density. Comparison of the effect of different firing patterns showed that phasic firing would increase the probability of reaching local DA levels sufficiently high to activate low-affinity DA receptors, mainly due to high DA levels transiently attained during the burst phase. The experimentally observed non-uniform surface distribution of DATs emerged as a major modulator of DA signaling: reuptake was slower, and the peaks/width of transient DA levels were sharper/wider under non-uniform distribution of DATs, compared to uniform. Overall, the study highlights the importance of accurate descriptions of extra-synaptic morphology, DAT distribution and conformational kinetics for quantitative evaluation of dopaminergic transmission and for providing deeper understanding of the mechanisms that regulate DA transmission.
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