3EE6

Crystal Structure Analysis of Tripeptidyl peptidase -I

Summary for 3EE6

• Entry DOI: 10.2210/pdb3ee6/pdb
• Descriptor: Tripeptidyl-peptidase 1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (7 entities in total)
• Functional Keywords: tripepetidyl peptidase -i, disease mutation, epilepsy, glycoprotein, hydrolase, lysosome, neuronal ceroid lipofuscinosis, protease, serine protease, zymogen
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 127389.69

Authors

Pal, A.,Kraetzner, R.,Grapp, M.,Gruene, T.,Schreiber, K.,Granborg, M.,Urlaub, H.,Asif, A.R.,Becker, S.,Gartner, J.,Sheldrick, G.M.,Steinfeld, R. (deposition date: 2008-09-04, release date: 2008-11-25, Last modification date: 2024-11-13)

Primary citation

Pal, A.,Kraetzner, R.,Gruene, T.,Grapp, M.,Schreiber, K.,Gronborg, M.,Urlaub, H.,Becker, S.,Asif, A.R.,Gartner, J.,Sheldrick, G.M.,Steinfeld, R.
Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis
J.Biol.Chem., 284:3976-3984, 2009

PubMed Abstract: 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.

PubMed: 19038966
DOI: 10.1074/jbc.M806947200

Experimental method

X-RAY DIFFRACTION (2.35 Å)