Substrate specificity and reaction mechanism of human prolidase

Wilk, P.; Uehlein, Monika; Kalms, Jacqueline; Dobbek, Holger; Muêller, U.; Weiss, M.S.

doi:10.1111/febs.14158

Cited by 33 publications

(59 citation statements)

References 71 publications

(104 reference statements)

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“…In Wilk et al . , we were also able to demonstrate that the Mn‐bridging water molecule is most likely activated to a more nucleophilic hydroxide ion, which facilitates peptide hydrolysis.…”

Section: Introductionmentioning

confidence: 69%

“…C). Just like in the wt‐ Hs Prol structure (PDB Id http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5M4G, ), the tightly bound Mn499 displays a stronger anomalous signal in the corresponding anomalous difference density peak than Mn500 (Table ).…”

Section: Resultsmentioning

confidence: 98%

“…Structure of the Arg184Gln variant of Hs Prol. (A) Location of the mutation site Arg184 in wt‐ Hs Prol ( PDB ‐Id 5M4J ) and its interaction with two Asp residues, which is likely stabilizing the loop containing the ligand‐binding His377. The substrate GlyPro is shown as ball‐and‐stick representation in black and the Na + ions as marine spheres.…”

Section: Resultsmentioning

confidence: 99%

“…The presence of both Mn 2+ ions in positions matching the ones observed in the wt‐ Hs Prol structure [PDB‐Id http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5M4G, ] can be ascertained by analyzing the corresponding anomalous difference electron density map. Mn499 and Mn500 appear at σ‐levels of roughly 55 and 70, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Overall structure of wt‐ Hs Prol. (A) Overall structure of the wt‐ Hs Prol dimer in complex with its preferred substrate GlyPro ( PDB ‐Id 5M4J ). The protein is depicted as ribbons (one subunit in yellow and the other one in white) and GlyPro as black spheres.…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for prolidase deficiency disease mechanisms

et al. 2018

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Section: Introductionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural basis for prolidase deficiency disease mechanisms

et al. 2018

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Crystal structures and biochemical analyses of intermediate cleavage peptidase: role of dynamics in enzymatic function

et al. 2019

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Intermediate cleavage peptidase (Icp55) processes a subset of mitochondrial matrix proteins by removing a bulky residue at their N termini, leaving behind smaller N‐terminal residues (icp activity). This contributes towards the stability of the mitochondrial proteome. We report crystal structures of yeast Icp55 including one bound to the apstatin inhibitor. Apart from icp activity, the enzyme was found to exhibit Xaa‐Pro aminopeptidase activity in vitro. Structural and biochemical data suggest that the enzyme exists in a rapid equilibrium between monomer and dimer. Furthermore, the dimer, and not the monomer, was found to be the active species with loop dynamics at the dimer interface playing an important role in activity. Based on the new evidence, we propose a model for binding and processing of cellular targets by Icp55. Database The atomic coordinates and structure factors for the structures of Icp55 (code http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6A9T, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6A9U, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6A9V) have been deposited in the Protein Data Bank (PDB) (http://www.pdb.org/).

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Co‐expression with chaperones can affect protein 3D structure as exemplified by loss‐of‐function variants of human prolidase

et al. 2020

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Prolidase catalyzes the cleavage of dipeptides containing proline on their C terminus. The reduction in prolidase activity is the cause of a rare disease named 'Prolidase Deficiency'. Local structural disorder was indicated as one of the causes for diminished prolidase activity. Previous studies showed that heat shock proteins can partially recover prolidase activity in vivo. To analyze this mechanism of enzymatic activity rescue, we compared the crystal structures of selected prolidase mutants expressed in the absence and in the presence of chaperones. Our results confirm that protein chaperones facilitate the formation of more ordered structures by their substrate protein. These results also suggest that the protein expression system needs to be considered as an important parameter in structural studies. Databases The reported crystal structures and their associated structure factor amplitudes were deposited in the Protein Data Bank under the accession codes http://6SRE, http://6SRF, and http://6SRG, respectively.

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Substrate specificity and reaction mechanism of human prolidase

Abstract: The refined structure coordinates as well as the corresponding structure factor amplitudes have been deposited in the PDB under the accession numbers 5M4G, 5M4J, 5M4L, and 5M4Q.

Cited by 33 publications

References 71 publications

Structural basis for prolidase deficiency disease mechanisms

Structural basis for prolidase deficiency disease mechanisms

Crystal structures and biochemical analyses of intermediate cleavage peptidase: role of dynamics in enzymatic function

Co‐expression with chaperones can affect protein 3D structure as exemplified by loss‐of‐function variants of human prolidase

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