Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a Drosophila model of TPI deficiency

Roland, Bartholomew P.; Amrich, Christopher G.; Kammerer, Charles J.; Stuchul, Kimberly A.; Larsen, Samantha B.; Rode, Sascha; Aslam, Anoshe A.; Heroux, Annie; Wetzel, Ronald; VanDemark, Andrew P.; Palladino, Michael J.

doi:10.1016/j.bbadis.2014.10.010

Title: Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a Drosophila model of TPI deficiency

Journal Article · Thu Oct 16 00:00:00 EDT 2014 · Biochimica et Biophysica Acta. Molecular Basis of Disease

DOI:https://doi.org/10.1016/j.bbadis.2014.10.010· OSTI ID:1281085

Roland, Bartholomew P. ^[1]; Amrich, Christopher G. ^[2]; Kammerer, Charles J. ^[1]; Stuchul, Kimberly A. ^[1]; Larsen, Samantha B. ^[1]; Rode, Sascha ^[3]; Aslam, Anoshe A. ^[2]; Heroux, Annie ^[4]; Wetzel, Ronald ^[3]; VanDemark, Andrew P. ^[5]; Palladino, Michael J. ^[1]

Univ. of Pittsburgh School of Medicine, PA (United States). Dept. of Pharmacology & Chemical Biology; Univ. of Pittsburgh School of Medicine, PA (United States). Pittsburgh Inst. for Neurodegenerative Diseases (PIND)
Univ. of Pittsburgh, PA (United States). Dept. of Biological Sciences
Univ. of Pittsburgh School of Medicine, PA (United States). Pittsburgh Inst. for Neurodegenerative Diseases (PIND); Univ. of Pittsburgh School of Medicine, PA (United States). Dept. of Structural Biology
Brookhaven National Lab. (BNL), Upton, NY (United States). Dept. of Biology
Univ. of Pittsburgh, PA (United States). Dept. of Biological Sciences; Univ. of Pittsburgh School of Medicine, PA (United States). Dept. of Structural Biology

Triosephosphate isomerase (TPI) is a glycolytic enzyme which homodimerizes for full catalytic activity. Mutations of the TPI gene elicit a disease known as TPI Deficiency, a glycolytic enzymopathy noted for its unique severity of neurological symptoms. Evidence suggests that TPI Deficiency pathogenesis may be due to conformational changes of the protein, likely affecting dimerization and protein stability. In this report, we genetically and physically characterize a human disease-associated TPI mutation caused by an I170V substitution. Human TPI^I170V elicits behavioral abnormalities in Drosophila. An examination of hTPI^I170V enzyme kinetics revealed this substitution reduced catalytic turnover, while assessments of thermal stability demonstrated an increase in enzyme stability. Furthermore, the crystal structure of the homodimeric I170V mutant reveals changes in the geometry of critical residues within the catalytic pocket. In the end, collectively these data reveal new observations of the structural and kinetic determinants of TPI deficiency pathology, providing new insights into disease pathogenesis.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: R01-GM103369 MJP; APV, R01-GM097204-APV; T32-GM8424-17 BPR

OSTI ID:: 1281085

Journal Information:: Biochimica et Biophysica Acta. Molecular Basis of Disease, Vol. 1852, Issue 1; ISSN 0925-4439

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 24 works

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Title: Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a Drosophila model of TPI deficiency

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