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2008

Fri, 12 Dec 2008
Comparative molecular dynamics simulations reveal the specificity of Bcl-XL anti-apoptotic protein

Time: 11.00 AM - 12.00 PM

Venue: Glycine, Level 7 (30 Biopolis Street, Matrix)

Speaker: Dr. R. Sankararamakrishnan, Indian Institute of Technology, Kanpur

Abstract

Apoptosis is one of the main types of programmed cell death. It is the physiological process of killing and removing damaged and unwanted surplus cells. This is implicated in several important biological processes, including embryogenesis, ageing and several cancers and neurodegerative diseases [1]. The Bcl-2 family of proteins is one of the well-characterized proteins and they play a central role in the regulation of mitochondrial pathway of apoptosis. Some of the Bcl-2 proteins are pro-apoptotic and others are anti-apoptotic. Heterodimerization of pro-and anti-apoptotic Bcl-2 proteins is a key event in apoptotic signaling. All Bcl-2 proteins have a remarkably similar helical fold in spite of poor amino acid sequence identity [2]. Bcl-XL is an anti-apoptotic protein and is expressed highly in many cancers [3-4]. It has different affinities for different pro-apoptotic partners. Bcl-XL s specificity for different pro-apoptotic Bcl-2 proteins at molecular level is not very well understood. Research on developing Bcl-XL inhibitors have mostly focused on the hydrophobic binding groove using the structure-based drug design approach. Experimentally determined structures of Bcl-XL complexed with BH3 peptides of pro-apoptotic Bak, Bad and Bim are available. In this work, we have highlighted the need to understand the dynamic features of the Bcl-2 proteins. We carried out 50 ns molecular dynamics simulations on the three Bcl-XL complex structures. Our studies demonstrate that the BH3 containing helix is flexible and partially unwind in all the simulations [5]. An Arg residue succeeding the conserved Leu in the BH3 region of pro-apoptotic proteins is implicated for the higher specificity of Bad andBim.

[1] Renehan et al. BMJ 322, 1536-1538 (2001)
[2] Petros et al. Biochim. Biophys. Acta 1644, 83-94 (2004)
[3] Veis et al. Cell 75, 229-240 (1993)
[4] Campos et al. Blood 81, 3091-3096 (1993)
[5] Lama and Sankararamakrishnan Proteins 73, 492-514 (2008)

About The Speaker
Dr. R. Sankararamakrishnan carried out his Ph. D work at Indian Institute of Science, Bangalore India. After his Ph. D, he received Wellcome Trust post-doctoral fellowship for a period of three years and joined at University of Oxford, U.K. His second post-doc was at Univ. Illinois, Urbana-Champaign, U.S.A. He then joined Mount Sinai School of Medicine, New York as a faculty and worked first as an Instructor and then as a Research Assistant Professor. In April 2002, Dr. Sankar joined the newly established Department of Biological Sciences and Bioengineering at Indian Institute of Technology, Kanpur. In January 2006, he was promoted to Associate Professor. Recently, he was awarded the Joy Gill Chair Professorship in his institute.

At IIT-Kanpur, he has established a strong Computational Biology group. Using various computational techniques, his group investigates protein-protein interactions, membrane proteins, novel-non-covalent interactions in proteins and alternate mechanisms in translation initiation.

Host
Dr. Madhusudhan Mallur Srivatsan, Research Scientist


 
 
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