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Search Results: 1 - 3 of 3 matches for " Nagakumar Bharatham "
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Molecular Basis of Bcl-XL-p53 Interaction: Insights from Molecular Dynamics Simulations
Nagakumar Bharatham, Seung-Wook Chi, Ho Sup Yoon
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026014
Abstract: Bcl-XL, an antiapoptotic Bcl-2 family protein, plays a central role in the regulation of the apoptotic pathway. Heterodimerization of the antiapoptotic Bcl-2 family proteins with the proapoptotic family members such as Bad, Bak, Bim and Bid is a crucial step in the apoptotic regulation. In addition to these conventional binding partners, recent evidences reveal that the Bcl-2 family proteins also interact with noncanonical binding partners such as p53. Our previous NMR studies showed that Bcl-XL: BH3 peptide and Bcl-XL: SN15 peptide (a peptide derived from residues S15-N29 of p53) complex structures share similar modes of bindings. To further elucidate the molecular basis of the interactions, here we have employed molecular dynamics simulations coupled with MM/PBSA approach. Bcl-XL and other Bcl-2 family proteins have 4 hydrophobic pockets (p1–p4), which are occupied by four systematically spaced hydrophobic residues (h1–h4) of the proapoptotic Bad and Bak BH3 peptides. We observed that three conserved hydrophobic residues (F19, W23 and L26) of p53 (SN15) peptide anchor into three hydrophobic pockets (p2–p4) of Bcl-XL in a similar manner as BH3 peptide. Our results provide insights into the novel molecular recognition by Bcl-XL with p53.
The Natively Disordered Loop of Bcl-2 Undergoes Phosphorylation-Dependent Conformational Change and Interacts with Pin1
CongBao Kang, Nagakumar Bharatham, Joel Chia, Yuguang Mu, Kwanghee Baek, Ho Sup Yoon
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052047
Abstract: Bcl-2 plays a central role in the regulation of apoptosis. Structural studies of Bcl-2 revealed the presence of a flexible and natively disordered loop that bridges the Bcl-2 homology motifs, BH3 and BH4. This loop is phosphorylated on multiple sites in response to a variety of external stimuli, including the microtubule-targeting drugs, paclitaxel and colchicine. Currently, the underlying molecular mechanism of Bcl-2 phosphorylation and its biological significance remain elusive. In this study, we investigated the molecular characteristics of this anti-apoptotic protein. To this end, we generated synthetic peptides derived from the Bcl-2 loop, and multiple Bcl-2 loop truncation mutants that include the phosphorylation sites. Our results demonstrate that S87 in the flexible loop of Bcl-2 is the primary phosphorylation site for JNK and ERK2, suggesting some sequence or structural specificity for the phosphorylation by these kinases. Our NMR studies and molecular dynamics simulation studies support indicate that phosphorylation of S87 induces a conformational change in the peptide. Finally, we show that the phosphorylated peptides of the Bcl-2 loop can bind Pin1, further substantiating the phosphorylation-mediated conformation change of Bcl-2.
Determinants, Discriminants, Conserved Residues - A Heuristic Approach to Detection of Functional Divergence in Protein Families
Kavitha Bharatham, Zong Hong Zhang, Ivana Mihalek
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024382
Abstract: In this work, belonging to the field of comparative analysis of protein sequences, we focus on detection of functional specialization on the residue level. As the input, we take a set of sequences divided into groups of orthologues, each group known to be responsible for a different function. This provides two independent pieces of information: within group conservation and overlap in amino acid type across groups. We build our discussion around the set of scoring functions that keep the two separated and the source of the signal easy to trace back to its source. We propose a heuristic description of functional divergence that includes residue type exchangeability, both in the conservation and in the overlap measure, and does not make any assumptions on the rate of evolution in the groups other than the one under consideration. Residue types acceptable at a certain position within an orthologous group are described as a distribution which evolves in time, starting from a single ancestral type, and is subject to constraints that can be inferred only indirectly. To estimate the strength of the constraints, we compare the observed degrees of conservation and overlap with those expected in the hypothetical case of a freely evolving distribution. Our description matches the experiment well, but we also conclude that any attempt to capture the evolutionary behavior of specificity determining residues in terms of a scalar function will be tentative, because no single model can cover the variety of evolutionary behavior such residues exhibit. Especially, models expecting the same type of evolutionary behavior across functionally divergent groups tend to miss a portion of information otherwise retrievable by the conservation and overlap measures they use.
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