NMR Studies of Human Apolipoprotein-E N-terminal Domain
EMSL Project ID
2299
Abstract
This research proposal is centered on NMR structural studies of human apolipoprotein-E (apoE). ApoE plays important roles in several human diseases, including atherosclerosis and Alzheimer’s diseases. We will particularly focus on solving the full-length apoE N-terminal domain, apoE(1-183). Although there is a X-ray crystal structure available for this domain, this structure only contains residue 23-166, whereas the rest of the regions have not yet been seen in the crystal structure (Wilson et al, 1991). Recent experimental data indicates that several residues beyond region 23-166 are critical in apoE LDL receptor binding activity (Weisgraber, 1991, 1994, Morrow et al, 2000). For example, mutation of residue 172 displays only 2% LDL receptor binding activity of apoE (Morrow, et al. 2000). Further, the truncation mutants 1-166 and 1-170 show only 1% LDL receptor binding activity, whereas the 1-174 variant possessed 17% normal binding activity (Weisgraber 1994). These results indicate that more structural studies of the apoE N-terminal domain are required to resolve these problems. The X-ray crystal structure indicates that residues beyond 23-164, either at the N-terminus or the C-terminus, are flexible and have no observable electron density map in the X-ray diffraction. Thus, NMR structural studies of the apoE N-terminal domain may provides a possible solution to these issues. Further, preliminary experimental evidence suggests that apoE(1-183) provides the complete LDL receptor binding activity for apoE (Weisgraber, 1994). We have 2H/15N/13C-triple labeled apoE(1-183) for 3D/4D heteronuclear NMR experiments. Our preliminary NMR studies indicated that apoE(1-183) adopted a similar helix-bundle structure at several different pHs, including pH6.4 and 3.2. Our NMR data further indicates the presence of NMR signals for those residues beyond 23-164 region, suggesting the possibility of a complete NMR assignment for intact apoE(1-183). In addition, this result also suggests that we may obtain a NMR structure of an intact apoE N-terminal domain in solution. We anticipate that a NMR structure of the intact apoE N-terminal domain may provide answers to the above important issues pertaining to the apoE LDL receptor binding activity.
Project Details
Project type
Capability Research
Start Date
2001-10-23
End Date
2002-08-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Abramson EH, D Imre, J Beranek, J Wilson, and A Zelenyuk. 2013. "Experimental Determination of Chemical Diffusion within Secondary Organic Aerosol Particles." Physical Chemistry Chemical Physics. PCCP 15(8):2983-2991. doi:10.1039/C2CP44013J
Chen B, X Ren, T Neville, WG Jerome, DW Hoyt, DL Sparks, G Ren, and J Wang. 2009. "Apolipoprotein AI tertiary structures determine stability and phospholipid-binding activity of discoidal high-density lipoprotein particles of different sizes." Protein Science 18(5):921-935. doi:10.1002/pro.101
Ferdinand C. Grozema, Stefano Tonzani, Yuri A. Berlin, George C. Schatz, Laurens D.A. Siebbeles and Mark A. Ratner
J. Am. Chem. Soc. (submitted)
Jennifer Tuma, Stefano Tonzani, George C. Schatz, Andrew H. Karaba, and Frederick D. Lewis
J. Phys. Chem. B 2007, 111, 13101
Lee HJ, KT McDonnell, A Zelenyuk, D Imre, and K Mueller. 2014. "A Structure-Based Distance Metric for High-Dimensional Space Exploration with Multi-Dimensional Scaling." IEEE Transactions on Visualization and Computer Graphics 20(3):351-364. doi:10.1109/TVCG.2013.101
Lin G, and AM Tartakovsky. 2009. "An efficient, high-order probabilistic collocation method on sparse grids for three-dimensional flow and solute transport in randomly heterogeneous porous media." Advances in Water Resources 32(5 SP ISS):712-722.
Papenhausen E, Wang B, Ha S, Zelenyuk A, Imre D, and Mueller K. 2013. "GPU-Accelerated Incremental Correlation Clustering of Large Data with Visual Feedback," The First Workshop on Big Data Visualization, Santa Clara, CA, October, 2013 doi:10.1109/BigData.2013.6691716
Stefano Tonzani and George C. Schatz
J. Am. Chem. Soc. (submitted)
Wang J ,Mueller K 2015. "The Visual Causality Analyst: An Interactive Interface for Causal Reasoning" IEEE Transactions on Visualization and Computer Graphics 22(1):230 - 239. 10.1109/TVCG.2015.2467931
Wang-yi Wu and Guang Lin. "Basic function scheme of polynomial type." Applied Mathematics and Mechanics, 2009, Volume 30, Number 9, Pages 1091-1103. DOI: 10.1007/s10483-009-0903-y
Xu C, A Sivashanmugam, DW Hoyt, and J Wang. 2005. "A Complete Backbone Assignment of the Apolipoprotein E LDL Receptor Binding Domain [Letter to the Editor]." Journal of Biomolecular NMR 32(2):177.
Zelenyuk A, D Imre, J Wilson, Z Zhang, J Wang, and K Mueller. 2015. "Airborne Single Particle Mass Spectrometers (SPLAT II & miniSPLAT) and New Software for Data Visualization and Analysis in a Geo-Spatial Context." Journal of The American Society for Mass Spectrometry:1-14. doi:10.1007/s13361-014-1043-4
Zhang Z, X Tong, KT McDonnell, A Zelenyuk, D Imre, and K Mueller. 2013. "An Interactive Visual Analytics Framework for Multi-Field Data in a Geo-Spatial Context." Tsinghua Science and Technology 18(2):111-124.
Zhiliang Xu, Guang Lin. "Spectral/HP element method with hierarchical reconstruction for solving nonlinear hyperbolic conservation laws". Acta Mathematica Scientia, Volume 29, Issue 6, November 2009, Pages 1737-1748