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Structural and functional implications of metal ion selection in aminopeptidase P, a metalloprotease with a dinuclear metal center.

Graham SC, Bond CS, Freeman HC, Guss JM
Biochemistry 44 13820-36 (2005)
Related entries: 1w2m, 1w7v, 1wbq, 1wl6, 1wlr, 2bh3, 2bha, 2bhb, 2bhc, 2bhd, 2bn7

Cited: 23 times
EuropePMC logo PMID: 16229471

Abstract

The effect of metal substitution on the activity and structure of the aminopeptidase P (APPro) from Escherichia coli has been investigated. Measurements of activity in the presence of Mn2+, Mg2+, Zn2+, Na+, and Ca2+ show that significant activity is seen only in the Mn-bound form of the enzyme. The addition of Zn2+ to [MnMn(APPro)] is strongly inhibitory. Crystal structures of [MnMn(APPro)], [MgMg(APPro)], [ZnZn(APPro)], [ZnMg(APPro)], [Ca_(APPro)], [Na_(APPro)], and [apo(APPro)] were determined. The structures of [Ca_(APPro)] and [Na_(APPro)] have a single metal atom at their active site. Surprisingly, when a tripeptide substrate (ValProLeu) was soaked into [Na_(APPro)] crystals in the presence of 200 mM Mg2+, the structure had substrate, but no metal, bound at the active site. The structure of apo APPro complexed with ValProLeu shows that the N-terminal amino group of a substrate can be bound at the active site by carboxylate side chains that normally bind the second metal atom, providing a model for substrate binding in a single-metal active enzyme. Structures of [MnMn(APPro)] and [ZnZn(APPro)] complexes of ProLeu, a product inhibitor, in the presence of excess Zn reveal a third metal-binding site, formed by two conserved His residues and the dipeptide inhibitor. A Zn atom bound at such a site would stabilize product binding and enhance inhibition.

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  2. P1' Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases. Talma M, Mucha A. Biomolecules 10 E659 (2020)
  3. A Molecular Analysis of the Aminopeptidase P-Related Domain of PID-5 from Caenorhabditis elegans. Lloyd AC, Gregory KS, Isaac RE, Acharya KR. Biomolecules 13 1132 (2023)


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  1. Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. O'Toole JF, Liu Y, Davis EE, Westlake CJ, Attanasio M, Otto EA, Seelow D, Nurnberg G, Becker C, Nuutinen M, Kärppä M, Ignatius J, Uusimaa J, Pakanen S, Jaakkola E, van den Heuvel LP, Fehrenbach H, Wiggins R, Goyal M, Zhou W, Wolf MT, Wise E, Helou J, Allen SJ, Murga-Zamalloa CA, Ashraf S, Chaki M, Heeringa S, Chernin G, Hoskins BE, Chaib H, Gleeson J, Kusakabe T, Suzuki T, Isaac RE, Quarmby LM, Tennant B, Fujioka H, Tuominen H, Hassinen I, Lohi H, van Houten JL, Rotig A, Sayer JA, Rolinski B, Freisinger P, Madhavan SM, Herzer M, Madignier F, Prokisch H, Nurnberg P, Jackson PK, Khanna H, Katsanis N, Hildebrandt F. J Clin Invest 120 791-802 (2010)
  2. Copper(I) and copper(II) inhibit Aβ peptides proteolysis by insulin-degrading enzyme differently: implications for metallostasis alteration in Alzheimer's disease. Grasso G, Pietropaolo A, Spoto G, Pappalardo G, Tundo GR, Ciaccio C, Coletta M, Rizzarelli E. Chemistry 17 2752-2762 (2011)
  3. FE(II) is the native cofactor for Escherichia coli methionine aminopeptidase. Chai SC, Wang WL, Ye QZ. J Biol Chem 283 26879-26885 (2008)
  4. Structural basis for catalysis by the mono- and dimetalated forms of the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase. Nocek BP, Gillner DM, Fan Y, Holz RC, Joachimiak A. J Mol Biol 397 617-626 (2010)
  5. Evidence for catalytic roles for Plasmodium falciparum aminopeptidase P in the food vacuole and cytosol. Ragheb D, Bompiani K, Dalal S, Klemba M. J Biol Chem 284 24806-24815 (2009)
  6. Biogenic manganese oxides as reservoirs of organic carbon and proteins in terrestrial and marine environments. Estes ER, Andeer PF, Nordlund D, Wankel SD, Hansel CM. Geobiology 15 158-172 (2017)
  7. Structure of a novel N-acetyl-L-citrulline deacetylase from Xanthomonas campestris. Shi D, Yu X, Roth L, Tuchman M, Allewell NM. Biophys Chem 126 86-93 (2007)
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  9. Structure-Function Relationship of Aminopeptidase P from Pseudomonas aeruginosa. Peng CT, Liu L, Li CC, He LH, Li T, Shen YL, Gao C, Wang NY, Xia Y, Zhu YB, Song YJ, Lei Q, Yu LT, Bao R. Front Microbiol 8 2385 (2017)
  10. A Mn(II)-Mn(II) center in human prolidase. Besio R, Baratto MC, Gioia R, Monzani E, Nicolis S, Cucca L, Profumo A, Casella L, Basosi R, Tenni R, Rossi A, Forlino A. Biochim Biophys Acta 1834 197-204 (2013)
  11. Complexes of mutants of Escherichia coli aminopeptidase P and the tripeptide substrate ValProLeu. Graham SC, Guss JM. Arch Biochem Biophys 469 200-208 (2008)
  12. Expression and characterization of the biofilm-related and carnosine-hydrolyzing aminoacylhistidine dipeptidase from Vibrio alginolyticus. Wang TY, Chen YC, Kao LW, Chang CY, Wang YK, Liu YH, Feng JM, Wu TK. FEBS J 275 5007-5020 (2008)
  13. Crystal structure of X-prolyl aminopeptidase from Caenorhabditis elegans: A cytosolic enzyme with a di-nuclear active site. Iyer S, La-Borde PJ, Payne KA, Parsons MR, Turner AJ, Isaac RE, Acharya KR. FEBS Open Bio 5 292-302 (2015)
  14. Using directed evolution to improve the solubility of the C-terminal domain of Escherichia coli aminopeptidase P. Implications for metal binding and protein stability. Liu JW, Hadler KS, Schenk G, Ollis D. FEBS J 274 4742-4751 (2007)
  15. Trichomonas vaginalis metalloproteinase TvMP50 is a monomeric Aminopeptidase P-like enzyme. Arreola R, Villalpando JL, Puente-Rivera J, Morales-Montor J, Rudiño-Piñera E, Alvarez-Sánchez ME. Mol Biotechnol 60 563-575 (2018)
  16. In silico characterization, docking, and simulations to understand host-pathogen interactions in an effort to enhance crop production in date palms. Alazmi M, Alshammari N, Alanazi NA, Sulieman AME. J Mol Model 27 339 (2021)
  17. Investigation of the proton relay system operative in human cystosolic aminopeptidase P. Chang HC, Kung CC, Chang TT, Jao SC, Hsu YT, Li WS, Li WS. PLoS One 13 e0190816 (2018)


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