Saravana P Thirumuruganandham

University of Alabama at Birmingham, Birmingham, Alabama, United States

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Publications (2)8.84 Total impact

  • Source
    Jere P Segrest · Martin K Jones · Andrea Catte · Saravana P Thirumuruganandham
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    ABSTRACT: LCAT is activated by apo A-I to form cholesteryl ester. We combined two structures-phospholipase A2 (PLA2), that hydrolyzes the ester bond at the sn-2 position of oxidized (short) acyl chains of phospholipid, and a bacteriophage, tubulin PhuZ-as C- and N-terminal templates, respectively, to create a novel homology model for human LCAT. The juxtaposition of multiple structural motifs matching experimental data is compelling evidence for the general correctness of many features of the model: i) The N-terminal ten residues of the model-required for LCAT activity-extend the hydrophobic binding trough for the sn-2 chain 15-20 Å relative to PLA2. ii) The topography of the trough places the ester bond of the sn-2 chain less than 5 Å from the hydroxyl of the catalytic nucleophile, S181. iii) A β-hairpin resembling a lipase lid separates S181 from solvent. iv) S181 interacts with three functionally critical residues: E149 that regulates sn-2 chain specificity and K128 and R147 whose mutations cause LCAT deficiency. Because the model provides a novel explanation for the complicated thermodynamic problem of the transfer of hydrophobic substrates from HDL to the catalytic triad of LCAT, it is an important step toward understanding the antiatherogenic role of HDL in reverse cholesterol transport. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    The Journal of Lipid Research 01/2015; 56(3). DOI:10.1194/jlr.M056382 · 4.42 Impact Factor
  • Jere P Segrest · Martin K Jones · Andrea Catte · Saravana P Thirumuruganandham
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    ABSTRACT: HDL is a population of apoA-I-containing particles inversely correlated with heart disease. Because HDL is a soft form of matter deformable by thermal fluctuations, structure determination has been difficult. Here, we compare the recently published crystal structure of lipid-free (Δ185-243)apoA-I with apoA-I structure from models and molecular dynamics (MD) simulations of discoidal HDL. These analyses validate four of our previous structural findings for apoA-I: i) a baseline double belt diameter of 105 Å ii) central α helixes with an 11/3 pitch; iii) a "presentation tunnel" gap between pairwise helix 5 repeats hypothesized to move acyl chains and unesterified cholesterol from the lipid bilayer to the active sites of LCAT; and iv) interchain salt bridges hypothesized to stabilize the LL5/5 chain registry. These analyses are also consistent with our finding that multiple salt bridge-forming residues in the N-terminus of apoA-I render that conserved domain "sticky." Additionally, our crystal MD comparisons led to two new hypotheses: i) the interchain leucine-zippers previously reported between the pair-wise helix 5 repeats drive lipid-free apoA-I registration; ii) lipidation induces rotations of helix 5 to allow formation of interchain salt bridges, creating the LCAT presentation tunnel and "zip-locking" apoA-I into its full LL5/5 registration.
    The Journal of Lipid Research 07/2012; 53(9):1851-63. DOI:10.1194/jlr.M026229 · 4.42 Impact Factor

Publication Stats

10 Citations
8.84 Total Impact Points


  • 2012–2015
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, Alabama, United States