Emerging biological functions of ribonuclease 1 and angiogenin

Garnett, Emily; Raines, Ronald T.

doi:10.1080/10409238.2021.2004577

Cited by 24 publications

(14 citation statements)

References 217 publications

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“…In fact, only in the third variant the Asp side chain provides proper interactions with the second catalytic His. The specific location of the C-terminus extension was associated to active site blockage and drastic decrease of catalytic activity in RNase 5, another family member, also called Angiogenin due to its angiogenic properties ( Garnett and Raines, 2021 ). Interestingly, Acharya and co-workers demonstrated how substitution of the C-terminus end in RNase 5 by the RNase 2 counterpart was able to remove the active site blockage ( Thiyagarajan and Acharya, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…Despite the potentially expensive cost of protein-based drugs respect to small molecules, novel methodologies have being developed to minimize the large scale production cost ( Gifre-Renom et al, 2018 ). RNases as cellular RNA metabolizing enzymes are attractive candidates for drug development ( Canestrari and Paroo, 2018 ; Garnett and Raines, 2021 ). Particular interest was drawn by members of the RNase A superfamily endowed with specific anti-infective properties that complement their catalytic properties ( Boix and Nogués, 2007 ; Rosenberg, 2008 ; Lu et al, 2018 ; Li and Boix, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Exploring the RNase A scaffold to combine catalytic and antimicrobial activities. Structural characterization of RNase 3/1 chimeras

Fernández-Millán

Vazquez-Monteagudo²,

Boix³

et al. 2022

Front. Mol. Biosci.

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Design of novel antibiotics to fight antimicrobial resistance is one of the first global health priorities. Novel protein-based strategies come out as alternative therapies. Based on the structure-function knowledge of the RNase A superfamily we have engineered a chimera that combines RNase 1 highest catalytic activity with RNase 3 unique antipathogen properties. A first construct (RNase 3/1-v1) was successfully designed with a catalytic activity 40-fold higher than RNase 3, but alas in detriment of its anti-pathogenic activity. Next, two new versions of the original chimeric protein were created showing improvement in the antimicrobial activity. Both second generation versions (RNases 3/1-v2 and -v3) incorporated a loop characteristic of RNase 3 (L7), associated to antimicrobial activity. Last, removal of an RNase 1 flexible loop (L1) in the third version enhanced its antimicrobial properties and catalytic efficiency. Here we solved the 3D structures of the three chimeras at atomic resolution by X-ray crystallography. Structural analysis outlined the key functional regions. Prediction by molecular docking of the protein chimera in complex with dinucleotides highlighted the contribution of the C-terminal region to shape the substrate binding cavity and determine the base selectivity and catalytic efficiency. Nonetheless, the structures that incorporated the key features related to RNase 3 antimicrobial activity retained the overall RNase 1 active site conformation together with the essential structural elements for binding to the human ribonuclease inhibitor (RNHI), ensuring non-cytotoxicity. Results will guide us in the design of the best RNase pharmacophore for anti-infective therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the RNase A scaffold to combine catalytic and antimicrobial activities. Structural characterization of RNase 3/1 chimeras

Fernández-Millán

Vazquez-Monteagudo²,

Boix³

et al. 2022

Front. Mol. Biosci.

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“…14,15 The interaction of CisPt with biomolecules in the plasma, especially in the cancer cell microenvironment, or the cytosol, may affect drug activity and availability. [16][17][18] Angiogenin (Ang), a protein of the ribonuclease superfamily, promotes angiogenesis and is strongly overexpressed in almost all human cancers; [19][20][21] its structure is made of three α-helices, seven β-strands, and a 3 10 helix (at the C-terminus) with the core stabilized by three disulfide bridges. 22 Ang partially maintains the RNase-A fold and shares with the pancreatic enzyme the same catalytic triad (His13, Lys40, and His114 in Ang).…”

Section: Introductionmentioning

confidence: 99%

Cisplatin binding to angiogenin protein: new molecular pathways and targets for the drug's anticancer activity

et al. 2023

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Section: Introductionmentioning

confidence: 99%

“…Human angiogenin (hAng; EC 3.1.27) is an atypical member of the RNase A superfamily composed of 123 residues . As its name implies, hAng is a potent inducer of neovascularization in physiological conditions and in several human malignancies. − Furthermore, its production from cancer cells seems to be regulated by HIF-1a, , implicating hAng in hypoxia-induced tumor neovascularization. Although the physiological substrate of hAng is not yet known, it has been shown to cleave tRNAs , to produce tiRNAs and miRNAs and to regulate rRNA expression. − Angiogenin’s enzymatic activity against simple RNA substrates is 10 –5 –10 –6 -fold lower than that of RNase A. , This is mostly attributed to the conformation of the C-terminus of hAng, which prevents any substrate from binding to the active site. , …”

Section: Introductionmentioning

confidence: 99%

Structural and Biochemical Characterization of the Human Angiogenin–Proliferating Cell Nuclear Antigen Interaction

et al. 2023

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The molecular details of the interaction between human angiogenin (hAng) and proliferating cell nuclear antigen (PCNA) have been investigated by isothermal titration calorimetry (ITC), mutagenesis, and NMR spectroscopy. The two proteins were shown to interact directly through immunoprecipitation studies of hAng with PCNA in vitro, and their interaction was quantified by ITC, obtaining information on stoichiometry, enthalpy, entropy, and binding kinetics of the association. The hAng−PCNA association is strong, with a K d value of 126 nM. The interaction surface was mapped by NMR spectroscopy, indicating participating residues. A structural model for the PCNA−hAng complex was constructed by docking and molecular dynamics simulations based on NMR data. The model was validated by mutating the hAng residues Arg5 and Arg101, which seem critical for the complex formation, to glutamate. ITC experiments showed that the angiogenin variants R5E and R5ER101E displayed 6.5 and 7.8 times higher K d values, respectively, than that of the native protein, indicating the correctness of the model. The hAng S28AT36AS37A and hAng S28AT36AS37AS87A variants were also tested as positive controls, further supporting the validity of the model. The crystal structures of the hAng variants S28AT36AS37A and S28AT36AS37AS87A showed that the mutations did not cause any significant conformational change. This study presents evidence for the structural mode of the hAng−PCNA interaction, revealing valuable information about the angiogenin and PCNA biological roles in the cytoplasm.

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Emerging biological functions of ribonuclease 1 and angiogenin

Cited by 24 publications

References 217 publications

Exploring the RNase A scaffold to combine catalytic and antimicrobial activities. Structural characterization of RNase 3/1 chimeras

Exploring the RNase A scaffold to combine catalytic and antimicrobial activities. Structural characterization of RNase 3/1 chimeras

Cisplatin binding to angiogenin protein: new molecular pathways and targets for the drug's anticancer activity

Structural and Biochemical Characterization of the Human Angiogenin–Proliferating Cell Nuclear Antigen Interaction

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