Abstract

This multi-disciplinary project will provide, for the first time, a detailed view of the structural and functional relationships between several key proteins and enzymes in lipid processing and metabolic pathways. Specifically, we will focus our efforts on investigating the muscle and intestinal fatty acid binding proteins (I-FABP) and the yeast and intestinal acyl CoA synthetases, four proteins involved in the intracellular fatty acid transfer pathway, as well as the ileal lipid binding protein and farnesyl pyrophosphate synthetase, proteins involved in sterol biosynthesis. Further studies will explore the structural and functional properties of a form of human I-FABP which is linked to insulin resistance and non- insulin dependent diabetes mellitus, NIDDM, in individuals that express this protein. Our studies will employ high resolution x-ray and neutron crystallography to determine the precise structures of the protein:water:lipid complexes we are studying. Differential scanning and titration calorimetry will be employed in order to analyze the energetics of lipid binding and protein stability. Site-directed mutagenesis will be utilized to dissect the role of specific amino acid sidechains in the chemical, thermodynamic and structural properties of proteins under investigation. Finally, kinetic analyses will permit us to determine the role of FABPs in the delivery of fatty acids to enzymes involved in fatty acid processing pathways.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM045859-07S1
Application #
2859574
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1991-09-01
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1999-08-31
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Texas A&M University
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
047006379
City
College Station
State
TX
Country
United States
Zip Code
77845

  Publications

Young, A C; Zhang, W; Sacchettini, J C et al. (1995) MHC class I-peptide interactions and TCR recognition. Cancer Surv 22:17-36
Young, A C; Nathenson, S G; Sacchettini, J C (1995) Structural studies of class I major histocompatibility complex proteins: insights into antigen presentation. FASEB J 9:26-36
Tarshis, L C; Yan, M; Poulter, C D et al. (1994) Crystal structure of recombinant farnesyl diphosphate synthase at 2.6-A resolution. Biochemistry 33:10871-7
Young, A C; Zhang, W; Sacchettini, J C et al. (1994) The three-dimensional structure of H-2Db at 2.4 A resolution: implications for antigen-determinant selection. Cell 76:39-50
Schreiber-Agus, N; Chin, L; Chen, K et al. (1994) Evolutionary relationships and functional conservation among vertebrate Max-associated proteins: the zebra fish homolog of Mxi1. Oncogene 9:3167-77
Mikami, B; Degano, M; Hehre, E J et al. (1994) Crystal structures of soybean beta-amylase reacted with beta-maltose and maltal: active site components and their apparent roles in catalysis. Biochemistry 33:7779-87
Young, A C; Scapin, G; Kromminga, A et al. (1994) Structural studies on human muscle fatty acid binding protein at 1.4 A resolution: binding interactions with three C18 fatty acids. Structure 2:523-34
Dewan, J C; Grant, G A; Sacchettini, J C (1994) Crystal structure of kappa-bungarotoxin at 2.3-A resolution. Biochemistry 33:13147-54
Scapin, G; Young, A C; Kromminga, A et al. (1993) High resolution X-ray studies of mammalian intestinal and muscle fatty acid-binding proteins provide an opportunity for defining the chemical nature of fatty acid: protein interactions. Mol Cell Biochem 123:3-13
Eads, J; Sacchettini, J C; Kromminga, A et al. (1993) Escherichia coli-derived rat intestinal fatty acid binding protein with bound myristate at 1.5 A resolution and I-FABPArg106-->Gln with bound oleate at 1.74 A resolution. J Biol Chem 268:26375-85

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