This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Intramembrane proteases are membrane-embedded proteases that cleave transmembrane (TM) substrates to liberate molecules that participate in important cellular processes, such as cell signaling. The GlpG intramembrane protease from E. coli is one of the best studied intramemembrane proteases. To dock its substrate, GlpG must open towards the lipid bilayer to admit the substrate. A lateral gate formed by the fifth helix of the protease apparently controls admission;motions of a loop near to the active site, denoted as the cap loop, may also assist substrate docking. An intriguing and little understood observation from experiments is that the composition of the lipid bilayer affects drastically the catalytic activity of GlpG: for example, phosphatidylethanolamine lipid headgroups, but not phosphatidylcholine, are compatible with catalytic substrate cleavage (Urban &Wolfe, 2005). Our molecular dynamics simulations on the <100ns timescale demonstrated that several loops of the protease, including the cap loop, undergo distinct conformational transitions that depend on the surrounding lipid headgroups (Bondar et al, 2009;Bondar &White, work in progress). For example, in a lipid bilayer composed of 1-palmytoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) the conformational transitions of the loops occur within 30ns and are almost simultaneous, whereas in 1-palmytoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE) the conformational transitions are clearly separated in time, and require up to 80ns. Due to the limited timescale of our simulations, we cannot exclude the possibility that the conformational transitions we observe are reversible, or that further conformational changes (e.g., opening of the lateral gate) could occur on the longer timescale. The microsecond-timescale simulations made possible by Anton will be invaluable for sampling and characterizing the lipid-dependent conformational transitions of GlpG as model system for intramembrane proteases in general.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
3P41RR006009-20S1
Application #
8364363
Study Section
Special Emphasis Panel (ZRG1-BCMB-Q (40))
Project Start
2011-09-15
Project End
2013-07-31
Budget Start
2011-09-15
Budget End
2013-07-31
Support Year
20
Fiscal Year
2011
Total Cost
$1,094
Indirect Cost
Name
Carnegie-Mellon University
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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