Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis
| Autor: | Kathrin Schreiber, Mads Grønborg, Jutta Gärtner, Robert Steinfeld, Aritra Pal, Tim Gruene, George M. Sheldrick, Marcel Grapp, Abdul R. Asif, Ralph Kraetzner, Stefan Becker, Henning Urlaub |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Protein Folding
Glycosylation Tripeptide Crystallography X-Ray Aminopeptidases Biochemistry Cell Line Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Neuronal Ceroid-Lipofuscinoses Endopeptidases Catalytic triad Hydrolase Humans Missense mutation Dipeptidyl-Peptidases and Tripeptidyl-Peptidases Molecular Biology Gene 030304 developmental biology 0303 health sciences Tripeptidyl-Peptidase 1 Chemistry Cell Biology Tripeptidyl peptidase I Protein Structure Tertiary N-terminus Structural Homology Protein Mutation Serine Proteases 030217 neurology & neurosurgery |
| Zdroj: | Journal of Biological Chemistry |
| Popis: | Late infantile neuronal ceroid lipofuscinosis, a fatal neurodegenerative disease of childhood, is caused by mutations in the TPP1 gene that encodes tripeptidyl-peptidase I. We show that purified TPP1 requires at least partial glycosylation for in vitro autoprocessing and proteolytic activity. We crystallized the fully glycosylated TPP1 precursor under conditions that implied partial autocatalytic cleavage between the prosegment and the catalytic domain. X-ray crystallographic analysis at 2.35 angstroms resolution reveals a globular structure with a subtilisin-like fold, a Ser475-Glu272-Asp360 catalytic triad, and an octahedrally coordinated Ca2+-binding site that are characteristic features of the S53 sedolisin family of peptidases. In contrast to other S53 peptidases, the TPP1 structure revealed steric constraints on the P4 substrate pocket explaining its preferential cleavage of tripeptides from the unsubstituted N terminus of proteins. Two alternative conformations of the catalytic Asp276 are associated with the activation status of TPP1. 28 disease-causing missense mutations are analyzed in the light of the TPP1 structure providing insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis. |
| Databáze: | OpenAIRE |
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