The major goal of the proposed research is to understand the molecular basis of lysosomal storage diseases, a collection of more than 40 inherited metabolic disorders that affect approximately 1 in 7,700 births. Lysosomal storage disorders are caused by defects in single genes, where the loss of a functional enzyme in the lysosome leads to accumulation of substrate and the development of disease symptoms. Lysosomal storage diseases are some of the best-understood members of the larger protein folding disease family, which includes disorders including Alzheimer's, Parkinson's, and Huntington's diseases. For a lysosomal enzyme to function correctly, a series of critical events must occur: after synthesis of a polypeptide, it must translocate into the Endoplasmic Reticulum (ER), where it must fold correctly;it must be post-translationally modified, allowing it to traffi through the Golgi apparatus to the lysosome;there, it must have the correct catalytic machinery and the stability to perform its enzymatic task. If there is a failure in any of these steps, the lysosomal enzyme will not function and disease will develop. Progress in the understanding and treatment of lysosomal storage diseases has been limited by the complexity of the pathway: a lysosomal storage disorder can develop due to failure of folding of the protein, failure of trafficking of the protein to the lysosome, or failure of the enzyme to function in the lysosome, etc. In order to better understand the development of lysosomal storage diseases and other protein folding diseases, we propose to study the folding, trafficking, and function of lysosomal enzymes. We propose to improve understanding of protein folding diseases by studying the molecular mechanism of pharmacological chaperoning in Fabry and Schindler diseases, by studying the structural basis of mucopolysaccharidosis, and the study of the structural basis of lysosomal trafficking. We propose to further knowledge and treatment of human disease by directly tackling difficult targets: human lysosomal enzymes, which are typically heavily glycosylated and otherwise post-translationally modified multimers.

Public Health Relevance

Lysosomal storage diseases are inherited metabolic diseases caused by a single defect in a single gene. We study these inherited diseases by discovering the three-dimensional shape of the proteins that are damaged in the diseases. This allows us to better understand how the diseases progress and how to better treat them.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK076877-06A1
Application #
8372720
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Mckeon, Catherine T
Project Start
2007-04-01
Project End
2016-05-31
Budget Start
2012-07-01
Budget End
2013-05-31
Support Year
6
Fiscal Year
2012
Total Cost
$285,766
Indirect Cost
$90,016
Name
University of Massachusetts Amherst
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
Taabazuing, Cornelius Y; Fermann, Justin; Garman, Scott et al. (2016) Substrate Promotes Productive Gas Binding in the α-Ketoglutarate-Dependent Oxygenase FIH. Biochemistry 55:277-86
Ferreira, Susana; Ortiz, Alberto; Germain, Dominique P et al. (2015) The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies. Mol Genet Metab 114:248-58
Ryan, Kelly C; Guce, Abigail I; Johnson, Olivia E et al. (2015) Nickel superoxide dismutase: structural and functional roles of His1 and its H-bonding network. Biochemistry 54:1016-27
Ferreira, Susana; Auray-Blais, Christiane; Boutin, Michel et al. (2015) Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma. Clin Chim Acta 447:96-104
Molla, Mijanur Rahaman; Marcinko, Tyler; Prasad, Priyaa et al. (2014) Unlocking a caged lysosomal protein from a polymeric nanogel with a pH trigger. Biomacromolecules 15:4046-53
Kolli, Nilima; Garman, Scott C (2014) Proteolytic activation of human cathepsin A. J Biol Chem 289:11592-600
Mohr, Benjamin G; Dobson, Cassidy M; Garman, Scott C et al. (2013) Electrostatic origin of in vitro aggregation of human ýý-crystallin. J Chem Phys 139:121914
Rivera-Colón, Yadilette; Schutsky, Emily K; Kita, Adriana Z et al. (2012) The structure of human GALNS reveals the molecular basis for mucopolysaccharidosis IV A. J Mol Biol 423:736-51
Clark, Nathaniel E; Metcalf, Matthew C; Best, Daniel et al. (2012) Pharmacological chaperones for human α-N-acetylgalactosaminidase. Proc Natl Acad Sci U S A 109:17400-5
Rood, Keith L; Clark, Nathaniel E; Stoddard, Patrick R et al. (2012) Adaptor-dependent degradation of a cell-cycle regulator uses a unique substrate architecture. Structure 20:1223-32

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