Hybrid molecular structure of the giant protease tripeptidyl peptidase II

Chuang, C. K.; Rockel, Beate; Seyit, Gönül; Walian, Peter J.; Schönegge, Anne–Marie; Peters, Jürgen; Zwart, Petrus H.; Baumeister, Wolfgang; Jap, Bing K.

doi:10.1038/nsmb.1870

Cited by 27 publications

(26 citation statements)

References 43 publications

(52 reference statements)

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“…Linear arrays of dimers form twisted strands that pair to form a spindle-shaped ∼6-MDa supercomplex that is stabilized by interactions between the terminal dimers (the double clamp) (14). The active sites are sequestered from the environment in "catalytic chambers" inaccessible for folded proteins (16). This basic architecture is conserved among eukaryotes from fission yeast to humans.…”

Section: Discussionmentioning

confidence: 99%

In situ structural studies of tripeptidyl peptidase II (TPPII) reveal spatial association with proteasomes

Fukuda

Beck

Plitzko

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Tripeptidyl peptidase II (TPPII) is a eukaryotic protease acting downstream of the 26S proteasome; it removes tripeptides from the degradation products released by the proteasome. Structural studies in vitro have revealed the basic architecture of TPPII, a twostranded linear polymer that assembles to form a spindle-shaped complex of ∼6 MDa. Dependent on protein concentration, TPPII has a distinct tendency for polymorphism. Therefore, its structure in vivo has remained unclear. To resolve this issue, we have scrutinized cryo-electron tomograms of rat hippocampal neurons for the occurrence and spatial distribution of TPPII by template matching. The quality of the tomograms recorded with the Volta phase plate enabled a detailed structural analysis of TPPII despite its low abundance. Two different assembly states (36-mers and 32-mers) coexist as well as occasional extended forms with longer strands. A distance analysis of the relative locations of TPPII and 26S proteasomes confirmed the visual impression that these two complexes spatially associate in agreement with TPPII's role in postproteasomal degradation.primary cultured neuronal cell | 26S proteasome | Volta phase plate | cryo-electron tomography | subtomogram averaging T he ubiquitin-proteasome system (UPS) is the main pathway of intracellular protein degradation in eukaryotic cells (1). In the UPS, the 26S proteasome, a 2.5-MDa multisubunit complex, degrades ubiquitylated proteins into oligopeptides with a size range of 4-25 residues (2, 3). The oligopeptides released by the 26S proteasome are further degraded by postproteasomal proteases (4, 5). One of the postproteasomal proteases that degrades oligopeptides longer than 15 residues is tripeptidyl peptidase II (TPPII) (6, 7). TPPII is a cytosolic serine protease of the subtilisin class (8) with an exopeptidase activity that removes tripeptides from free N-termini of peptides (9). TPPII has also been reported to be endowed with endopeptidase activity, but this activity is very low compared with its exopeptidase activity (10). Previously, only unfolded peptides had been reported to be degraded by TPPII (11). Tripeptides produced by TPPII are thought to be hydrolyzed further by an array of aminopeptidases (12). In addition to protein turnover, a role in MHC class 1 antigen presentation has also been proposed as one of the cellular functions of TPPII, but is still a subject of some controversy [for a review see Rockel et al. (11)]. A membrane-associated version of TPPII functions as a neuropeptidase inactivating the satiety hormone cholecystokinin-8 (CCK-8) by degrading into CCK-5 in the rat brain (13).Structural studies of isolated and purified TPPII revealed the existence of large (∼6 MDa) spindle-shaped complexes comprising two linear arrays of 20 monomers each in Drosophila melanogaster (14) and 18 monomers each in Homo sapiens (15). High-resolution structures of Drosophila TPPII (16) and human TPPII (15) have been obtained by hybrid approaches combining X-ray crystallography and EM single-particle analysis...

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Section: Discussionmentioning

confidence: 99%

In situ structural studies of tripeptidyl peptidase II (TPPII) reveal spatial association with proteasomes

Fukuda

Beck

Plitzko

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…TPP II is a large, 6 MDa structure comprising two segmented twisted strands, each composed of 10 dimers made up of identical 138 kDa subunits [21]. The recent elucidation of its 3.2 Å structure revealed how stacking of these dimer subunits leads to the priming and sequestration of the catalytic sites into chambers [22]. In inactive dimers, the substrate binding site is occluded by a three-residue loop, the positioning of which displaces the active-site serine.…”

Section: The Controversial Role Of Tripeptidyl Peptidase IImentioning

confidence: 99%

“…At the same time, a network of chambers providing multiple access pathways to the active site is formed. Assembled TPP II can be compared to a ''molecular sponge'' with a very high local concentration of active sites [22]. TPP II has attracted the attention of cancer biologists because of its upregulation and function in tumor cells [23].…”

Section: The Controversial Role Of Tripeptidyl Peptidase IImentioning

confidence: 99%

Post-proteasomal and proteasome-independent generation of MHC class I ligands

Endert

2011

Cell. Mol. Life Sci.

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Peptide ligands presented by MHC class I molecules are produced by intracellular proteolysis, which often involves multiple steps. Initial antigen degradation seems to rely almost invariably on the proteasome, although tripeptidyl peptidase II (TPP II) and insulin-degrading enzyme (IDE) may be able to substitute for the proteasome in rare cases. Recent evidence suggests that the net effect of cytosolic aminopeptidases is destruction of potential class I ligands, although a positive role in selected cases has been documented. This may apply particularly to the trimming of long precursors by TPP II. In contrast, trimming of ligand precursors in the endoplasmic reticulum is essential for the generation of suitable peptides and has a substantial impact on the repertoire of ligands presented. Trimming by the ER aminopeptidase (ERAP) enzymes most likely acts on free precursors and is adapted to the needs of class I molecules by way of a molecular ruler mechanism. Trimming by ERAP enzymes also occurs for cross-presented ligands, which can alternatively be processed in a special endosomal compartment by insulin-regulated aminopeptidase.

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“…TPPII has also been reported to possess endoproteolytic activity but this function remains poorly characterized. TPPII subunits can assemble into higher order, spindle-shaped giant peptidase complexes of 6 MDa, thus forming the largest known protease complex in eukaryotic cells [26]. TPPII has been implicated in cancer and has been shown to be upregulated in c-MYC-associated Burkitt lymphoma cells [27].…”

Section: Introductionmentioning

confidence: 99%

Tripeptidyl Peptidase II Is Required for c-MYC-Induced Centriole Overduplication and a Novel Therapeutic Target in c-MYC-Associated Neoplasms

Duensing

Darr²,

Cuevas³

et al. 2010

Genes & Cancer

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Centrosome aberrations are frequently detected in c-MYC-associated human malignancies. Here, we show that c-MYC-induced centrosome and centriole overduplication critically depend on the protease tripeptidyl peptidase II (TPPII). We found that TPPII localizes to centrosomes and that overexpression of TPPII, similar to c-MYC, can disrupt centriole duplication control and cause centriole multiplication, a process during which maternal centrioles nucleate the formation of more than a single daughter centriole. We report that inactivation of TPPII using chemical inhibitors or siRNA-mediated protein knock-down effectively reduced c-MYC-induced centriole overduplication. Remarkably, the potent and selective TPPII inhibitor butabindide not only potently suppressed centriole aberrations but also caused significant cell death and growth suppression in aggressive human Burkitt lymphoma cells with c-MYC overexpression. Taken together, these results highlight the role of TPPII in c-MYC-induced centriole overduplication and encourage further studies to explore TPPII as a novel antineoplastic drug target.

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Hybrid molecular structure of the giant protease tripeptidyl peptidase II

Cited by 27 publications

References 43 publications

In situ structural studies of tripeptidyl peptidase II (TPPII) reveal spatial association with proteasomes

In situ structural studies of tripeptidyl peptidase II (TPPII) reveal spatial association with proteasomes

Post-proteasomal and proteasome-independent generation of MHC class I ligands

Tripeptidyl Peptidase II Is Required for c-MYC-Induced Centriole Overduplication and a Novel Therapeutic Target in c-MYC-Associated Neoplasms

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