Limits...
Molecular basis of Bcl-X(L)-p53 interaction: insights from molecular dynamics simulations.

Bharatham N, Chi SW, Yoon HS - PLoS ONE (2011)

Bottom Line: Bcl-X(L) 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-X(L) in a similar manner as BH3 peptide.Our results provide insights into the novel molecular recognition by Bcl-X(L) with p53.

View Article: PubMed Central - PubMed

Affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore.

ABSTRACT
Bcl-X(L), 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-X(L): BH3 peptide and Bcl-X(L): 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-X(L) 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-X(L) in a similar manner as BH3 peptide. Our results provide insights into the novel molecular recognition by Bcl-X(L) with p53.

Show MeSH
Hydrophobic and charged surface of Bcl-XL.The shallow hydrophobic pocket of Bcl-XL is shown with yellow color, positive and negatively charged residues present on the walls of the pocket represented with blue and red, respectively. The hydrophobic residues of peptides h1–h4 of Bad (A), Bak (B) and h2–h4 of SN15 (C) are highlighted as sticks which lock with hydrophobic pockets of Bcl-XL. Complimentary charged residues on Bad (D), Bak (E), SN15 (F) are highlighted as sticks and labeled accordingly.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3198449&req=5

pone-0026014-g005: Hydrophobic and charged surface of Bcl-XL.The shallow hydrophobic pocket of Bcl-XL is shown with yellow color, positive and negatively charged residues present on the walls of the pocket represented with blue and red, respectively. The hydrophobic residues of peptides h1–h4 of Bad (A), Bak (B) and h2–h4 of SN15 (C) are highlighted as sticks which lock with hydrophobic pockets of Bcl-XL. Complimentary charged residues on Bad (D), Bak (E), SN15 (F) are highlighted as sticks and labeled accordingly.

Mentions: Both Bad and Bak peptides consists of two negatively charged successive amino acids (D17, E18 in Bad and D12 and D13 in Bak). These residues extend their side chains and cover both sides of the Bcl-XL binding pocket charged walls (Figure 5D and 5E). They superimpose well in both the peptide binding conformations and are suspected to form hydrogen bond as well as salt bridge interactions with R139 and R100, respectively. But only in the case of Bak peptide both aspartate residues interact with arginine residues by either hydrogen bond interactions or salt bridges. This observation was clearly reflected in the residual decomposition analysis (Table 7). Both arginines R100 and R139 contributed predominantly (−3.5 and −5.1 kcal/mol, respectively), but the Bad peptide is not able to interact with these residues. The possible reason could be due to unfavorable interactions with R139 because of close proximity to another positively charged residue R13 on Bad peptide which causes charge repulsion. E18 is unable to form any type of interactions with R100; instead it forms a hydrogen bonding interaction with Y101. Residue Q16 of SN15 forms 2–3 hydrogen bond interactions with Bcl-XL. Main chain carbonyl group interacts with R100 and its side chain form hydrogen bonds with E96 side chain of the protein. Because of these two interactions E96 and R100 contributed favorably for complex formation (Figure S3).


Molecular basis of Bcl-X(L)-p53 interaction: insights from molecular dynamics simulations.

Bharatham N, Chi SW, Yoon HS - PLoS ONE (2011)

Hydrophobic and charged surface of Bcl-XL.The shallow hydrophobic pocket of Bcl-XL is shown with yellow color, positive and negatively charged residues present on the walls of the pocket represented with blue and red, respectively. The hydrophobic residues of peptides h1–h4 of Bad (A), Bak (B) and h2–h4 of SN15 (C) are highlighted as sticks which lock with hydrophobic pockets of Bcl-XL. Complimentary charged residues on Bad (D), Bak (E), SN15 (F) are highlighted as sticks and labeled accordingly.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198449&req=5

pone-0026014-g005: Hydrophobic and charged surface of Bcl-XL.The shallow hydrophobic pocket of Bcl-XL is shown with yellow color, positive and negatively charged residues present on the walls of the pocket represented with blue and red, respectively. The hydrophobic residues of peptides h1–h4 of Bad (A), Bak (B) and h2–h4 of SN15 (C) are highlighted as sticks which lock with hydrophobic pockets of Bcl-XL. Complimentary charged residues on Bad (D), Bak (E), SN15 (F) are highlighted as sticks and labeled accordingly.
Mentions: Both Bad and Bak peptides consists of two negatively charged successive amino acids (D17, E18 in Bad and D12 and D13 in Bak). These residues extend their side chains and cover both sides of the Bcl-XL binding pocket charged walls (Figure 5D and 5E). They superimpose well in both the peptide binding conformations and are suspected to form hydrogen bond as well as salt bridge interactions with R139 and R100, respectively. But only in the case of Bak peptide both aspartate residues interact with arginine residues by either hydrogen bond interactions or salt bridges. This observation was clearly reflected in the residual decomposition analysis (Table 7). Both arginines R100 and R139 contributed predominantly (−3.5 and −5.1 kcal/mol, respectively), but the Bad peptide is not able to interact with these residues. The possible reason could be due to unfavorable interactions with R139 because of close proximity to another positively charged residue R13 on Bad peptide which causes charge repulsion. E18 is unable to form any type of interactions with R100; instead it forms a hydrogen bonding interaction with Y101. Residue Q16 of SN15 forms 2–3 hydrogen bond interactions with Bcl-XL. Main chain carbonyl group interacts with R100 and its side chain form hydrogen bonds with E96 side chain of the protein. Because of these two interactions E96 and R100 contributed favorably for complex formation (Figure S3).

Bottom Line: Bcl-X(L) 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-X(L) in a similar manner as BH3 peptide.Our results provide insights into the novel molecular recognition by Bcl-X(L) with p53.

View Article: PubMed Central - PubMed

Affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore.

ABSTRACT
Bcl-X(L), 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-X(L): BH3 peptide and Bcl-X(L): 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-X(L) 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-X(L) in a similar manner as BH3 peptide. Our results provide insights into the novel molecular recognition by Bcl-X(L) with p53.

Show MeSH