Abstract

This is a pilot and feasibility proposal to develop femtosecond-pulse two-dimensional infrared correlation spectroscopy (IR-COSY) as a tool for structure determination in the amyloid beta proteins that form parallel beta sheet fibrils, and are difficult to study by the traditional methods of structural biology. The approach will also be applied to study the evolution of such structure during fibrillogenesis. ? ? Alzheimer's disease and several others are now recognized to involve the misfolding and aggregation of proteins as parallel beta sheets. A better understanding of this pathological protein structure is key to understanding why these proteins misfold in the first place, and to developing therapeutic interventions for these diseases. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM076201-01A2
Application #
7258536
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Basavappa, Ravi
Project Start
2007-04-15
Project End
2010-03-31
Budget Start
2007-04-15
Budget End
2008-03-31
Support Year
1
Fiscal Year
2007
Total Cost
$236,063
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Furman, Ran; Lee, Jin V; Axelsen, Paul H (2018) Analysis of eicosanoid oxidation products in Alzheimer brain by LC-MS with uniformly 13C-labeled internal standards. Free Radic Biol Med 118:108-118
Grasso, Giuseppe; Axelsen, Paul H (2017) Effects of covalent modification by 4-hydroxy-2-nonenal on the noncovalent oligomerization of ubiquitin. J Mass Spectrom 52:36-42
Lee, Jin V; Furman, Ran; Axelsen, Paul H (2017) Biosynthesis of uniformly labeled13C- and14C-arachidonic acid in Mortierella alpina. Bioresour Technol 227:142-146
Eskici, Gözde; Axelsen, Paul H (2016) The Size of AOT Reverse Micelles. J Phys Chem B 120:11337-11347
Furman, Ran; Murray, Ian V J; Schall, Hayley E et al. (2016) Amyloid Plaque-Associated Oxidative Degradation of Uniformly Radiolabeled Arachidonic Acid. ACS Chem Neurosci 7:367-77
Klinger, Alexandra L; Kiselar, Janna; Ilchenko, Serguei et al. (2014) A synchrotron-based hydroxyl radical footprinting analysis of amyloid fibrils and prefibrillar intermediates with residue-specific resolution. Biochemistry 53:7724-34
Ma, Jianqiang; Komatsu, Hiroaki; Kim, Yung Sam et al. (2013) Intrinsic structural heterogeneity and long-term maturation of amyloid ? peptide fibrils. ACS Chem Neurosci 4:1236-43
Yeung, Priscilla S-W; Eskici, Gözde; Axelsen, Paul H (2013) Infrared spectroscopy of proteins in reverse micelles. Biochim Biophys Acta 1828:2314-8
Yeung, Priscilla S-W; Axelsen, Paul H (2012) The crowded environment of a reverse micelle induces the formation of ?-strand seed structures for nucleating amyloid fibril formation. J Am Chem Soc 134:6061-3
Kim, Yung Sam; Liu, Liu; Axelsen, Paul H et al. (2009) 2D IR provides evidence for mobile water molecules in beta-amyloid fibrils. Proc Natl Acad Sci U S A 106:17751-6

Showing the most recent 10 out of 11 publications