Calcium-Mediated Control Of S100 Proteins: Allosteric Communication Via An Agitator/Signal Blocking Mechanism
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY(2017)
摘要
Allosteric proteins possess dynamically coupled residues for the propagation of input signals to distant target binding sites. The input signals usually correspond to "effector is present" or "effector is not present". Many aspects of allosteric regulation remain incompletely understood. This work focused on S100A11, a dimeric EF-hand protein with two hydrophobic target binding sites. An annexin peptide (Ax) served as the target. Target binding is allosterically controlled by Ca2+ over a distance of similar to 26 A. Ca2+ promotes formation of a [Ca-4 5100 Axe] complex, where the Ax peptides are accommodated between helices III/W and III'/IV'. Without Ca2+ these binding sites are closed, precluding interactions with Ax. The allosteric mechanism was probed by microsecond MD simulations in explicit water, complemented by hydrogen exchange mass spectrometry (HDX/MS). Consistent with experimentai data, MD runs in the absence-of Ca2+ and- Ax culminated in target binding site closure. In-Simulations on [Ca-4 SIOQ]: the target binding sites remained open:. These-results capture the essence of allosteric control, revealing how Ca2+ prevents binding site closure. Both HDX/IVIS and MD data Showed that the rnetalation sites become more dynamic after Ca2+ loss. However, these enhanced dynamics do not represent the primary trigger of the allosteric cascade. Instead,,a labile salt bridge acts as an incessantly active agitator that destabilizes the packing of adjacent residues, causing a domino chain of events That, culminates in target binding site closure. This agitator represents the, Starting point of the allosteric signal propagation pathway.. Ca2+ binding rigidifies elements along this pathway, thereby blocking signal transmission. This blocking mechanism does not conform to the calm-Amity held view that allosteric commnunication pathways generally originate at the sites where effectors interact with the protein.
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