Publications
65 results found
Heller GT, Aprile FA, Bonomi M, et al., 2019, Probing Specificity in Disordered Protein Interactions with Small Molecules using Integrative Methods, 63rd Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 180A-180A, ISSN: 0006-3495
Sormanni P, Aprile FA, Vendruscolo M, 2018, Third generation antibody discovery methods: <i>in silico</i> rational design, CHEMICAL SOCIETY REVIEWS, Vol: 47, Pages: 9137-9157, ISSN: 0306-0012
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- Citations: 64
Perni M, Casford S, Aprile FA, et al., 2018, Automated Behavioral Analysis of Large <i>C</i>. <i>elegans</i> Populations Using a Wide Field-of-view Tracking Platform, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X
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- Citations: 6
Giorgetti S, Greco C, Tortora P, et al., 2018, Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 19
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- Citations: 91
Giorgetti S, Greco C, Tortora P, et al., 2018, Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms
<jats:p>Amyloids result from the aggregation of several unrelated proteins, due to either specific mutations or promoting intra- or extra-cellular conditions. Structurally, they are rich in intermolecular &beta;-sheets and are the causative agents of several diseases, both neurodegenerative and systemic. It is believed that the most toxic species are small aggregates, referred to as oligomers, rather than the final fibrillar assemblies. Their mechanisms of toxicity are mostly mediated by aberrant interactions with the cell membranes, with resulting derangement of membrane-related functions. Much effort is being put in the search for natural antiamyloid agents, and/or in the development of synthetic molecules. Actually, it is well documented that the prevention of amyloid aggregation results in several cytoprotective effects. Here, we portray the state of the art in the field. Several natural compounds are effective antiamyloid agents, notably tetracyclines and polyphenols. They are generally non-specific, as documented by their partially overlapping mechanisms, and the capability to interfere with the aggregation of several unrelated proteins. Among rationally designed molecules, we mention the prominent examples of &beta;-breakers peptides, whole antibodies and fragments thereof, and the special case of drugs contrasting transthyretin aggregation. In this framework, we stress the pivotal role of the computational approaches. When combined with biophysical methods, in several cases they have helped clarify in detail the protein/drug modes of interaction, which make it plausible that more effective drugs will be developed in the future.</jats:p>
Perni M, Flagmeier P, Limbocker R, et al., 2018, Multistep Inhibition of α-Synuclein Aggregation and Toxicity <i>in Vitro</i> and <i>in Vivo</i> by Trodusquemine, ACS CHEMICAL BIOLOGY, Vol: 13, Pages: 2308-2319, ISSN: 1554-8929
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- Citations: 72
Wright MA, Aprile FA, Bellaiche MMJ, et al., 2018, Cooperative Assembly of Hsp70 Subdomain Clusters, BIOCHEMISTRY, Vol: 57, Pages: 3641-3649, ISSN: 0006-2960
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- Citations: 8
Bongiovanni MN, Aprile FA, Sormanni P, et al., 2018, A Rationally Designed Hsp70 Variant Rescues the Aggregation-Associated Toxicity of Human IAPP in Cultured Pancreatic Islet β-Cells., Int J Mol Sci, Vol: 19
Molecular chaperones are key components of the protein homeostasis system against protein misfolding and aggregation. It has been recently shown that these molecules can be rationally modified to have an enhanced activity against specific amyloidogenic substrates. The resulting molecular chaperone variants can be effective inhibitors of protein aggregation in vitro, thus suggesting that they may provide novel opportunities in biomedical and biotechnological applications. Before such opportunities can be exploited, however, their effects on cell viability should be better characterised. Here, we employ a rational design method to specifically enhance the activity of the 70-kDa heat shock protein (Hsp70) against the aggregation of the human islet amyloid polypeptide (hIAPP, also known as amylin). We then show that the Hsp70 variant that we designed (grafted heat shock protein 70 kDa-human islet amyloid polypeptide, GHsp70-hIAPP) is significantly more effective than the wild type in recovering the viability of cultured pancreatic islet β-cells RIN-m5F upon hIAPP aggregation. These results indicate that a full recovery of the toxic effects of hIAPP aggregates on cultured pancreatic cells can be achieved by increasing the specificity and activity of Hsp70 towards hIAPP, thus providing evidence that the strategy presented here provides a possible route for rationally tailoring molecular chaperones for enhancing their effects in a target-dependent manner.
Bonanomi M, Roffia V, De Palma A, et al., 2018, The polyglutamine protein ataxin-3 enables normal growth under heat shock conditions in the methylotrophic yeast <i>Pichia pastoris</i> (vol 7, 2017), SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322
Perni M, Aprile FA, Casford S, et al., 2017, Delivery of Native Proteins into <i>C-elegans</i> Using a Transduction Protocol Based on Lipid Vesicles, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
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- Citations: 14
Bonanomi M, Roffia V, De Palma A, et al., 2017, The polyglutamine protein ataxin-3 enables normal growth under heat shock conditions in the methylotrophic yeast <i>Pichia pastoris</i>, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
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- Citations: 1
Bertoldo JB, Rodrigues T, Dunsmore L, et al., 2017, A Water-Bridged Cysteine-Cysteine Redox Regulation Mechanism in Bacterial Protein Tyrosine Phosphatases, CHEM, Vol: 3, Pages: 665-677, ISSN: 2451-9294
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- Citations: 15
Heller GT, Aprilel FA, Bonomi M, et al., 2017, Sequence Specificity in the Entropy-Driven Binding of a Small Molecule and a Disordered Peptide, JOURNAL OF MOLECULAR BIOLOGY, Vol: 429, Pages: 2772-2779, ISSN: 0022-2836
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- Citations: 48
Heller GT, Aprile FA, Vendruscolo M, 2017, Methods of probing the interactions between small molecules and disordered proteins, CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 74, Pages: 3225-3243, ISSN: 1420-682X
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- Citations: 47
Aprile FA, Kallstig E, Limorenko G, et al., 2017, The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
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- Citations: 52
Aprile FA, Sormanni P, Perni M, et al., 2017, Selective targeting of primary and secondary nucleation pathways in Aβ42 aggregation using a rational antibody scanning method, SCIENCE ADVANCES, Vol: 3, ISSN: 2375-2548
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- Citations: 90
Sin O, de Jong T, Mata-Cabana A, et al., 2017, Identification of an RNA Polymerase III Regulator Linked to Disease-Associated Protein Aggregation, MOLECULAR CELL, Vol: 65, Pages: 1096-+, ISSN: 1097-2765
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- Citations: 9
Aprile FA, Arosio P, Fusco G, et al., 2017, Inhibition of α-Synuclein Fibril Elongation by Hsp70 Is Governed by a Kinetic Binding Competition between α-Synuclein Species, BIOCHEMISTRY, Vol: 56, Pages: 1177-1180, ISSN: 0006-2960
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- Citations: 40
Perni M, Galvagnion C, Maltsev A, et al., 2017, A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 114, Pages: E1009-E1017, ISSN: 0027-8424
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- Citations: 207
Borkar AN, Bardaro MF, Camilloni C, et al., 2016, Structure of a low-population binding intermediate in protein-RNA recognition, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 113, Pages: 7171-7176, ISSN: 0027-8424
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- Citations: 48
Arosio P, Hu K, Aprile FA, et al., 2016, Microfluidic Diffusion Viscometer for Rapid Analysis of Complex Solutions, ANALYTICAL CHEMISTRY, Vol: 88, Pages: 3488-3493, ISSN: 0003-2700
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- Citations: 27
Arosio P, Mueller T, Rajah L, et al., 2016, Microfluidic Diffusion Analysis of the Sizes and Interactions of Proteins under Native Solution Conditions, ACS NANO, Vol: 10, Pages: 333-341, ISSN: 1936-0851
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- Citations: 68
Wright MA, Aprile FA, Arosio P, et al., 2015, Biophysical approaches for the study of interactions between molecular chaperones and protein aggregates, CHEMICAL COMMUNICATIONS, Vol: 51, Pages: 14425-14434, ISSN: 1359-7345
Nimmervoll B, Chtcheglova LA, Juhasz K, et al., 2015, Cell surface localised Hsp70 is a cancer specific regulator of clathrin-independent endocytosis, FEBS LETTERS, Vol: 589, Pages: 2747-2753, ISSN: 0014-5793
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- Citations: 30
Aprile FA, Sormanni P, Vendruscolo M, 2015, A Rational Design Strategy for the Selective Activity Enhancement of a Molecular Chaperone toward a Target Substrate, BIOCHEMISTRY, Vol: 54, Pages: 5103-5112, ISSN: 0006-2960
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- Citations: 24
Sormanni P, Aprile FA, Vendruscolo M, 2015, Rational design of antibodies targeting specific epitopes within intrinsically disordered proteins, Proceedings of the National Academy of Sciences of the United States of America, Vol: 112, Pages: 9902-9907, ISSN: 0027-8424
Antibodies are powerful tools in life sciences research, as well as in diagnostic and therapeutic applications, because of their ability to bind given molecules with high affinity and specificity. Using current methods, however, it is laborious and sometimes difficult to generate antibodies to target specific epitopes within a protein, in particular if these epitopes are not effective antigens. Here we present a method to rationally design antibodies to enable them to bind virtually any chosen disordered epitope in a protein. The procedure consists in the sequence-based design of one or more complementary peptides targeting a selected disordered epitope and the subsequent grafting of such peptides on an antibody scaffold. We illustrate the method by designing six single-domain antibodies to bind different epitopes within three disease-related intrinsically disordered proteins and peptides (α-synuclein, Aβ42, and IAPP). Our results show that all these designed antibodies bind their targets with good affinity and specificity. As an example of an application, we show that one of these antibodies inhibits the aggregation of α-synuclein at substoichiometric concentrations and that binding occurs at the selected epitope. Taken together, these results indicate that the design strategy that we propose makes it possible to obtain antibodies targeting given epitopes in disordered proteins or protein regions.
Chen SW, Drakulic S, Deas E, et al., 2015, Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 112, Pages: E1994-E2003, ISSN: 0027-8424
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- Citations: 337
Kukic P, Leung HTA, Bemporad F, et al., 2015, Structure and Dynamics of the Integrin LFA-1 I-Domain in the Inactive State Underlie its Inside-Out/Outside-In Signaling and Allosteric Mechanisms, STRUCTURE, Vol: 23, Pages: 745-753, ISSN: 0969-2126
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- Citations: 15
Sormanni P, Aprile FA, Vendruscolo M, 2015, The CamSol Method of Rational Design of Protein Mutants with Enhanced Solubility, JOURNAL OF MOLECULAR BIOLOGY, Vol: 427, Pages: 478-490, ISSN: 0022-2836
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- Citations: 243
De Simone A, Aprile FA, Dhulesia A, et al., 2015, Structure of a low-population intermediate state in the release of an enzyme product., eLife, Vol: 4, ISSN: 2050-084X
Enzymes can increase the rate of biomolecular reactions by several orders of magnitude. Although the steps of substrate capture and product release are essential in the enzymatic process, complete atomic-level descriptions of these steps are difficult to obtain because of the transient nature of the intermediate conformations, which makes them largely inaccessible to standard structure determination methods. We describe here the determination of the structure of a low-population intermediate in the product release process by human lysozyme through a combination of NMR spectroscopy and molecular dynamics simulations. We validate this structure by rationally designing two mutations, the first engineered to destabilise the intermediate and the second to stabilise it, thus slowing down or speeding up, respectively, product release. These results illustrate how product release by an enzyme can be facilitated by the presence of a metastable intermediate with transient weak interactions between the enzyme and product.
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