The long unstructured region of Bcl‐xl modulates its structural dynamics

Abstract

Bcl-xl protein has a long unstructured loop attached to its structured region which joins two helices. The necessity to have this unstructured segment in Bcl-xl is not yet well understood. To what extent the unstructured segment can influence the dynamics of the structured region of protein, with potential to influence the function, has been investigated in this work. Molecular dynamics simulation and principal component analysis show how the loop affects the internal motions of the protein, particularly its ligand binding pocket. Generally an unstructured region in the structure would promote flexibility resulting entropic stability but in contrary, here it narrows down the conformational space of the structured region of protein that could be hypothesized to impact the functional precision. Effects of the loop propagate to the binding pocket through structural rearrangements of polar side chains. The immediate suspicion of possible impact of phosphorylation to modulate the function of the protein is proven to be a fact, as the phosphorylated S49 and S62 located on the large unstructured region are seen to perturb the electrostatic network of the structure; an observation that validates and clarifies the role of loop as a modulator through biophysical and biochemical mechanisms. Proteins 2017; 85:1567-1579. © 2017 Wiley Periodicals, Inc.

Impact of lymphoma‐linked Asn11Tyr point mutation on the interaction between Bcl‐2 and a BH3 mimetic: Insights from molecular dynamics simulation

“…In the porcupine plots (Figure 7), the direction of the arrow in each Cα atom characterizes the direction of the movement, while the length of the arrow represents the magnitude of the motion. The results from the eigenvector analysis of the wild-type Bcl-2 were consistent with the report published by Priya, Maity, and Ghosh (2017). Our results suggest that the concerted motion (captured by PC1, PC2, and PC3) between the two models is varied to a large extent, implicating the effect of mutation on the dynamic properties of the Bcl-2/43B binding.…”

Impact of deamidation on the structure and function of anti-apoptotic Bcl-xL.

“…Priya et al 53 in their computational study (100 ns ×2 in total for Bcl-xL with IDR) had reported transient interactions between the IDR and the core region of the Bcl-xL. In line with the findings of Priya et al, most of our simulations for WT and DM1 show that the loop residues E31, E32, E39 and R78 temporarily interact with core residues R165, R6, R91, and E7, respectively.…”

“…Priya et al also reported that R103 (J23) and R139 (α5) of wild-type Bcl-xL behave like a gate by covering the bottom side of the binding groove compared to that of Bcl-xL without IDR. 53 We observed this type of behavior in DM1-SIM1, alas, between different residues. Most prominently, in DM1-SIM1, R102 on J23 persistently interacts with D133 (J45) (77.1 %) and E129 (α4) (45.8 %) indicating the importance of the R102 residue (Fig.…”

“…However, the model used by Maity et al was truncated by removing the Bak peptide from its complex with Bcl-xL (PDB ID: 1BXLNMR), moreover, the IDR was not present. In 2017 Priya et al 53 investigated the influence of the IDR on the function of Bcl-xL by comparing Bcl-xL with and without the IDR (total 800 ns, NPT simulations). They showed that the IDR allosterically modulates the structural dynamics of Bcl-xL and they validated this finding through testing the effect of phosphorylation of S49 and S62 in the IDR.…”

BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians

“…At the post-translational level, BCL-xL can be phosphorylated, deamidated, and ubiquitinated. Phosphorylation of BCL-xL at Ser-62 and Ser-49, have been well characterized and can alter BCL-xL intracellular localization and its loop conformation [32], which regulates the molecular association with other proteins such as BH3-only proteins and p53 [23]. Interestingly, BCL-xL proteins undergo dynamic phosphorylation/dephosphorylation on Ser-49 and Ser-62 residues during mitosis are important in the maintenance of chromosome integrity in normal cells [33].…”