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From Proteopedia
Crystal Structure of the Precursor Form of Human Tripeptidyl-Peptidase 1
Structural highlights
Disease[TPP1_HUMAN] Defects in TPP1 are the cause of neuronal ceroid lipofuscinosis type 2 (CLN2) [MIM:204500]. A form of neuronal ceroid lipofuscinosis. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The lipopigment pattern seen most often in CLN2 consists of curvilinear profiles.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Function[TPP1_HUMAN] Lysosomal serine protease with tripeptidyl-peptidase I activity. May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases. Requires substrates with an unsubstituted N-terminus (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedLate 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 A 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. Crystal Structure and Autoactivation Pathway of the Precursor Form of Human Tripeptidyl-peptidase 1, the Enzyme Deficient in Late Infantile Ceroid Lipofuscinosis.,Guhaniyogi J, Sohar I, Das K, Stock AM, Lobel P J Biol Chem. 2009 Feb 6;284(6):3985-97. Epub 2008 Nov 26. PMID:19038967[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Tripeptidyl-peptidase I | Das, K | Guhaniyogi, J | Lobel, P | Sohar, I | Stock, A M | Batten disease | Catalytic triad | Cln2 | Disease mutation | Endopeptidase | Epilepsy | Exopeptidase | Glycoprotein | Hydrolase | Lincl | Lysosome | Neuronal ceroid lipofuscinosis | Oxyanion hole | Prodomain | Protease | S53 family | Sedolisin | Serine protease | Tpp1 | Zymogen
