3EE6

Crystal Structure Analysis of Tripeptidyl peptidase -I

3EE6 の概要

• エントリーDOI: 10.2210/pdb3ee6/pdb
• 分子名称: Tripeptidyl-peptidase 1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (7 entities in total)
• 機能のキーワード: tripepetidyl peptidase -i, disease mutation, epilepsy, glycoprotein, hydrolase, lysosome, neuronal ceroid lipofuscinosis, protease, serine protease, zymogen
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 127389.69

構造登録者

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. (登録日: 2008-09-04, 公開日: 2008-11-25, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.35 Å)