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Institute for Advanced Simulation (IAS)

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Seminar by Jun-Prof. Dr. Bettina Keller

Freie Universität Berlin (Germany)

begin
14 Sep 2016 16:00
end
14 Sep 2016 17:00
venue
Lecture room 2009, Jülich GRS building (16.15)

The function of the cell-surface receptor Langerin relies on an Ca2+ ion which acts as a co-factor. It is released from the protein after a drop of pH from 7.4 to 6 to 6.5 during endocytosis. We could show that the pH sensitivity is generated by two pH sensors, a histidine residue at position 294 (H294) and a glytamyl-dyade in the Ca2+ binding site. However, with an estimated pKa of 5 to 6, these pH sensors are only weakly sensitive to the targeted pH change. From molecular dynamics simulations, we quantified the non-linear correlations in Langerin as the mutual information between residue pairs. This analysis revealed an allosteric network in which the long loop, which is part of the binding site, is connected to a more distant short loop via a single edge. If one of the nodes at this bridge is mutated, the connection between the long-loop and the short loop in the mutual information graph is lost, the average distance between the two loops in the simulation increases and their correlation time decreases. The experimentally determined Ca2+ affinity in this mutant is increased. Thus, the allosteric network downregulates the overall Ca2+ affinity by restraining the dynamics of the long loop. With a decreased overall affinity, a partial protonation of the pH sensor is then sufficient to release the Ca2+ ion. The results are in excellent agreement with chemical shifts perturbations upon Ca2+ binding observed in HSQC NMR experiments.

This analysis shows how allosteric networks can be elucidated by molecular dynamics simulation and mutual information analysis. It also shows that allosteric networks may not only serve to transmit signals in protein but also to regulate the response of the protein to the a change in the surrounding solvent.


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