3EDY

Crystal Structure of the Precursor Form of Human Tripeptidyl-Peptidase 1

Summary for 3EDY

• Entry DOI: 10.2210/pdb3edy/pdb
• Descriptor: Tripeptidyl-peptidase 1, CALCIUM ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: protease, tpp1, sedolisin, batten disease, lincl, zymogen, prodomain, exopeptidase, endopeptidase, s53 family, cln2, catalytic triad, oxyanion hole, disease mutation, epilepsy, glycoprotein, hydrolase, lysosome, neuronal ceroid lipofuscinosis, serine protease
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome : O14773
• Total number of polymer chains: 1
• Total formula weight: 60542.30

Authors

Guhaniyogi, J.,Sohar, I.,Das, K.,Lobel, P.,Stock, A.M. (deposition date: 2008-09-03, release date: 2008-11-18, Last modification date: 2024-10-30)

Primary citation

Guhaniyogi, J.,Sohar, I.,Das, K.,Stock, A.M.,Lobel, P.
Crystal Structure and Autoactivation Pathway of the Precursor Form of Human Tripeptidyl-peptidase 1, the Enzyme Deficient in Late Infantile Ceroid Lipofuscinosis
J.Biol.Chem., 284:3985-3997, 2009

PubMed Abstract: Late infantile neuronal ceroid lipofuscinosis is a fatal childhood neurological disorder caused by a deficiency in the lysosomal protease tripeptidyl-peptidase 1 (TPP1). TPP1 represents the only known mammalian member of the S53 family of serine proteases, a group characterized by a subtilisin-like fold, a Ser-Glu-Asp catalytic triad, and an acidic pH optimum. TPP1 is synthesized as an inactive proenzyme (pro-TPP1) that is proteolytically processed into the active enzyme after exposure to low pH in vitro or targeting to the lysosome in vivo. In this study, we describe an endoglycosidase H-deglycosylated form of TPP1 containing four Asn-linked N-acetylglucosamines that is indistinguishable from fully glycosylated TPP1 in terms of autocatalytic processing of the proform and enzymatic properties of the mature protease. The crystal structure of deglycosylated pro-TPP1 was determined at 1.85 angstroms resolution. A large 151-residue C-shaped prodomain makes extensive contacts as it wraps around the surface of the catalytic domain with the two domains connected by a 24-residue flexible linker that passes through the substrate-binding groove. The proenzyme structure reveals suboptimal catalytic triad geometry with its propiece linker partially blocking the substrate-binding site, which together serve to prevent premature activation of the protease. Finally, we have identified numerous processing intermediates and propose a structural model that explains the pathway for TPP1 activation in vitro. These data provide new insights into TPP1 function and represent a valuable resource for constructing improved TPP1 variants for treatment of late infantile neuronal ceroid lipofuscinosis.

PubMed: 19038967
DOI: 10.1074/jbc.M806943200

Experimental method

X-RAY DIFFRACTION (1.85 Å)