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Article ; Online: Structure, Oligomerization and Activity Modulation in N-Ribohydrolases.

Degano, Massimo

International journal of molecular sciences

2022 Volume 23, Issue 5

Abstract: Enzymes catalyzing the hydrolysis of the N-glycosidic bond in nucleosides and other ribosides (N-ribohydrolases, NHs) with diverse substrate specificities are found in all kingdoms of life. While the overall NH fold is highly conserved, limited ... ...

Abstract	Enzymes catalyzing the hydrolysis of the N-glycosidic bond in nucleosides and other ribosides (N-ribohydrolases, NHs) with diverse substrate specificities are found in all kingdoms of life. While the overall NH fold is highly conserved, limited substitutions and insertions can account for differences in substrate selection, catalytic efficiency, and distinct structural features. The NH structural module is also employed in monomeric proteins devoid of enzymatic activity with different physiological roles. The homo-oligomeric quaternary structure of active NHs parallels the different catalytic strategies used by each isozyme, while providing a buttressing effect to maintain the active site geometry and allow the conformational changes required for catalysis. The unique features of the NH catalytic strategy and structure make these proteins attractive targets for diverse therapeutic goals in different diseases.
MeSH term(s)	Catalysis ; Catalytic Domain ; Crystallography, X-Ray ; Models, Molecular ; Nucleosides ; Substrate Specificity
Chemical Substances	Nucleosides
Language	English
Publishing date	2022-02-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23052576
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Article ; Online: Author Correction: Direct and high throughput (HT) interactions on the ribosomal surface by iRIA.

Pesce, Elisa / Minici, Claudia / Baßler, Jochen / Hurt, Ed / Degano, Massimo / Calamita, Piera / Biffo, Stefano

Scientific reports

2023 Volume 13, Issue 1, Page(s) 1938

Language	English
Publishing date	2023-02-02
Publishing country	England
Document type	Published Erratum
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-28876-7
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Article ; Online: A riboside hydrolase that salvages both nucleobases and nicotinamide in the auxotrophic parasite Trichomonas vaginalis.

Patrone, Marco / Galasyn, Gregory S / Kerin, Fiona / Nyitray, Mattias M / Parkin, David W / Stockman, Brian J / Degano, Massimo

The Journal of biological chemistry

2023 Volume 299, Issue 9, Page(s) 105077

Abstract: Pathogenic parasites of the Trichomonas genus are causative agents of sexually transmitted diseases affecting millions of individuals worldwide and whose outcome may include stillbirths and enhanced cancer risks and susceptibility to HIV infection. ... ...

Abstract	Pathogenic parasites of the Trichomonas genus are causative agents of sexually transmitted diseases affecting millions of individuals worldwide and whose outcome may include stillbirths and enhanced cancer risks and susceptibility to HIV infection. Trichomonas vaginalis relies on imported purine and pyrimidine nucleosides and nucleobases for survival, since it lacks the enzymatic activities necessary for de novo biosynthesis. Here we show that T. vaginalis additionally lacks homologues of the bacterial or mammalian enzymes required for the synthesis of the nicotinamide ring, a crucial component in the redox cofactors NAD
MeSH term(s)	Animals ; Hydrolases/chemistry ; Hydrolases/metabolism ; NAD/metabolism ; Niacinamide/metabolism ; Parasites ; Trichomonas vaginalis/enzymology ; Crystallography, X-Ray ; Substrate Specificity ; Protein Structure, Tertiary ; Models, Molecular ; Protein Binding
Chemical Substances	Hydrolases (EC 3.-) ; NAD (0U46U6E8UK) ; Niacinamide (25X51I8RD4) ; nicotinamide-beta-riboside (0I8H2M0L7N)
Language	English
Publishing date	2023-07-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.105077
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Article ; Online: Type 1 Diabetes in STAT Protein Family Mutations: Regulating the Th17/Treg Equilibrium and Beyond.

Fabbri, Marco / Frixou, Mikaela / Degano, Massimo / Fousteri, Georgia

Diabetes

2019 Volume 68, Issue 2, Page(s) 258–265

Abstract: Improvements in the immunological, molecular, and genetic technologies such as next-generation sequencing have led to an exponential increase in the number of monogenic immune dysregulatory syndromes diagnosed, where type 1 diabetes (T1D) forms part of ... ...

Abstract	Improvements in the immunological, molecular, and genetic technologies such as next-generation sequencing have led to an exponential increase in the number of monogenic immune dysregulatory syndromes diagnosed, where type 1 diabetes (T1D) forms part of the autoimmune manifestations. Here, we reviewed the mutations in the signal transducer and activator of transcription (STAT) protein family, namely gain-of-function (GOF) mutations in
MeSH term(s)	Animals ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism ; Humans ; Mutation/genetics ; STAT1 Transcription Factor/genetics ; STAT3 Transcription Factor/genetics ; T-Lymphocytes, Regulatory/metabolism ; Th17 Cells/metabolism
Chemical Substances	STAT1 Transcription Factor ; STAT3 Transcription Factor
Language	English
Publishing date	2019-01-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db18-0627
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Article ; Online: Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor.

Patrone, Marco / Cammarota, Eugenia / Berno, Valeria / Tornaghi, Paola / Mazza, Davide / Degano, Massimo

Communications biology

2020 Volume 3, Issue 1, Page(s) 27

Abstract: The structural plasticity of G-protein coupled receptors (GPCRs) enables the long-range transmission of conformational changes induced by specific orthosteric site ligands and other pleiotropic factors. Here, we demonstrate that the ligand binding cavity ...

Abstract	The structural plasticity of G-protein coupled receptors (GPCRs) enables the long-range transmission of conformational changes induced by specific orthosteric site ligands and other pleiotropic factors. Here, we demonstrate that the ligand binding cavity in the sphingosine 1-phosphate receptor S1PR1, a class A GPCR, is in allosteric communication with both the β-arrestin-binding C-terminal tail, and a receptor surface involved in oligomerization. We show that S1PR1 oligomers are required for full response to different agonists and ligand-specific association with arrestins, dictating the downstream signalling kinetics. We reveal that the active form of the immunomodulatory drug fingolimod, FTY720-P, selectively harnesses both these intramolecular networks to efficiently recruit β-arrestins in a stable interaction with the receptor, promoting deep S1PR1 internalization and simultaneously abrogating ERK1/2 phosphorylation. Our results define a molecular basis for the efficacy of fingolimod for people with multiple sclerosis, and attest that GPCR signalling can be further fine-tuned by the oligomeric state.
MeSH term(s)	Allosteric Regulation ; Cell Line ; Cell Membrane/metabolism ; Fingolimod Hydrochloride/chemistry ; Fingolimod Hydrochloride/pharmacology ; Humans ; Kinetics ; Models, Molecular ; Phosphorylation ; Proprotein Convertases/chemistry ; Proprotein Convertases/metabolism ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Protein Transport ; Receptors, G-Protein-Coupled/agonists ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/metabolism ; Serine Endopeptidases/chemistry ; Serine Endopeptidases/metabolism ; Signal Transduction ; Structure-Activity Relationship ; beta-Arrestins/chemistry ; beta-Arrestins/metabolism
Chemical Substances	Receptors, G-Protein-Coupled ; beta-Arrestins ; Proprotein Convertases (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-) ; membrane-bound transcription factor peptidase, site 1 (EC 3.4.21.112) ; Fingolimod Hydrochloride (G926EC510T)
Language	English
Publishing date	2020-01-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-020-0752-4
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Article ; Online: Structures of catalytic cycle intermediates of the Pyrococcus furiosus methionine adenosyltransferase demonstrate negative cooperativity in the archaeal orthologues.

Minici, Claudia / Mosca, Laura / Ilisso, Concetta Paola / Cacciapuoti, Giovanna / Porcelli, Marina / Degano, Massimo

Journal of structural biology

2020 Volume 210, Issue 1, Page(s) 107462

Abstract: Methionine adenosyltransferases catalyse the biosynthesis of S-adenosylmethionine, the primary methyl group donor in biochemical reactions, through the condensation of methionine and ATP. Here, we report the structural analysis of the Pyrococcus furiosus ...

Abstract	Methionine adenosyltransferases catalyse the biosynthesis of S-adenosylmethionine, the primary methyl group donor in biochemical reactions, through the condensation of methionine and ATP. Here, we report the structural analysis of the Pyrococcus furiosus methionine adenosyltransferase (PfMAT) captured in the unliganded, substrate- and product-bound states. The conformational changes taking place during the enzymatic catalytic cycle are allosterically propagated by amino acid residues conserved in the archaeal orthologues to induce an asymmetric dimer structure. The distinct occupancy of the active sites within a PfMAT dimer is consistent with a half-site reactivity that is mediated by a product-induced negative cooperativity. The structures of intermediate states of PfMAT reported here suggest a distinct molecular mechanism for S-adenosylmethionine synthesis in Archaea, likely consequence of the evolutionary pressure to achieve protein stability under extreme conditions.
MeSH term(s)	Binding Sites ; Catalysis ; Crystallography, X-Ray/methods ; Methionine Adenosyltransferase/chemistry ; Methionine Adenosyltransferase/metabolism ; Protein Conformation ; Pyrococcus furiosus/enzymology ; Pyrococcus furiosus/metabolism
Chemical Substances	Methionine Adenosyltransferase (EC 2.5.1.6)
Language	English
Publishing date	2020-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1032718-6
ISSN	1095-8657 ; 1047-8477
ISSN (online)	1095-8657
ISSN	1047-8477
DOI	10.1016/j.jsb.2020.107462
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Article ; Online: Disease-associated mutations in the coil 2B domain of human lamin A/C affect structural properties that mediate dimerization and intermediate filament formation.

Gangemi, Fabrizio / Degano, Massimo

Journal of structural biology

2013 Volume 181, Issue 1, Page(s) 17–28

Abstract: The lamin proteins are essential components of the nuclear lamina of eukaryotic cells, that are involved in a complex association mechanism to attain a functional supermolecular structure. Mutations of the lamin A/C gene are associated with several ... ...

Abstract	The lamin proteins are essential components of the nuclear lamina of eukaryotic cells, that are involved in a complex association mechanism to attain a functional supermolecular structure. Mutations of the lamin A/C gene are associated with several different neuromuscular diseases, and the detailed effect of disease-associated amino acid substitutions on the structure and stability of human lamin dimers is yet unknown. Here we present a structural and thermodynamic characterization by means of molecular dynamics simulations of the effect of pathological mutations (S326T, R331P, R331Q, E347K, E358K, M371K, and R377H) on the association of the coil 2B domains that mediate lamin A/C oligomerization. The structures attained during the simulations, along with the quantification of the contribution of each residue to the dimerization energies, support a lamin association mechanism mediated by homophilic intermolecular interactions promoted by dissociative conformational changes at distinct positions in the coiled coil. The pathogenic mutations can both increase or decrease the stability of lamin A/C dimers, and a possible correlation between the effect of the amino acid substitutions and disease onset and severity is presented.
MeSH term(s)	Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Intermediate Filaments ; Lamin Type A/chemistry ; Lamin Type A/genetics ; Molecular Dynamics Simulation ; Mutation, Missense ; Neuromuscular Diseases/genetics ; Protein Binding ; Protein Multimerization ; Protein Stability ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Thermodynamics
Chemical Substances	LMNA protein, human ; Lamin Type A
Language	English
Publishing date	2013-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1032718-6
ISSN	1095-8657 ; 1047-8477
ISSN (online)	1095-8657
ISSN	1047-8477
DOI	10.1016/j.jsb.2012.10.016
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Article: A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer.

Zuppone, Stefania / Assalini, Chiara / Minici, Claudia / Botrugno, Oronza A / Curnis, Flavio / Degano, Massimo / Corti, Angelo / Montorsi, Francesco / Salonia, Andrea / Vago, Riccardo

Frontiers in oncology

2022 Volume 12, Page(s) 846958

Abstract: Although toxin may have some advantages compared to chemotherapeutic drugs in cancer therapy, e.g. a potent cytotoxic activity and a reduced risk of resistance, their successful application in the treatments to solid tumors still remains to be fully ... ...

Abstract	Although toxin may have some advantages compared to chemotherapeutic drugs in cancer therapy, e.g. a potent cytotoxic activity and a reduced risk of resistance, their successful application in the treatments to solid tumors still remains to be fully demonstrated. In this study, we genetically modified the structure of the plant-derived single-chain ribosome inactivating protein saporin (SAP) by fusing its N-terminus to the ACDCRGDCFCG peptide (RGD-4C), an αv-integrin ligand, and explored the anti-tumor activity of the resulting protein (called RGD-SAP)
Language	English
Publishing date	2022-04-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.846958
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Article ; Online: Role of Disputed Mutations in the

Miotto, Paolo / Cabibbe, Andrea M / Borroni, Emanuele / Degano, Massimo / Cirillo, Daniela M

Journal of clinical microbiology

2018 Volume 56, Issue 5

Abstract: Low-level rifampin resistance associated with ... ...

Abstract	Low-level rifampin resistance associated with specific
MeSH term(s)	Antibiotics, Antitubercular/pharmacology ; DNA-Directed RNA Polymerases/genetics ; Genotype ; Humans ; Microbial Sensitivity Tests ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Retrospective Studies ; Rifampin/pharmacology ; Time Factors ; Tuberculosis/microbiology
Chemical Substances	Antibiotics, Antitubercular ; DNA-Directed RNA Polymerases (EC 2.7.7.6) ; RNA polymerase beta subunit (EC 2.7.7.6) ; Rifampin (VJT6J7R4TR)
Language	English
Publishing date	2018-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	390499-4
ISSN	1098-660X ; 0095-1137
ISSN (online)	1098-660X
ISSN	0095-1137
DOI	10.1128/JCM.01599-17
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Article ; Online: N-Glycosylation of the Ig Receptors Shapes the Antigen Reactivity in Chronic Lymphocytic Leukemia Subset #201.

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 211, Issue 5, Page(s) 743–754

Abstract: Subset #201 is a clinically indolent subgroup of patients with chronic lymphocytic leukemia defined by the expression of stereotyped, mutated IGHV4-34/IGLV1-44 BCR Ig. Subset #201 is characterized by recurrent somatic hypermutations (SHMs) that ... ...

Abstract	Subset #201 is a clinically indolent subgroup of patients with chronic lymphocytic leukemia defined by the expression of stereotyped, mutated IGHV4-34/IGLV1-44 BCR Ig. Subset #201 is characterized by recurrent somatic hypermutations (SHMs) that frequently lead to the creation and/or disruption of N-glycosylation sites within the Ig H and L chain variable domains. To understand the relevance of this observation, using next-generation sequencing, we studied how SHM shapes the subclonal architecture of the BCR Ig repertoire in subset #201, particularly focusing on changes in N-glycosylation sites. Moreover, we profiled the Ag reactivity of the clonotypic BCR Ig expressed as rmAbs. We found that almost all analyzed cases from subset #201 carry SHMs potentially affecting N-glycosylation at the clonal and/or subclonal level and obtained evidence for N-glycan occupancy in SHM-induced novel N-glycosylation sites. These particular SHMs impact (auto)antigen recognition, as indicated by differences in Ag reactivity between the authentic rmAbs and germline revertants of SHMs introducing novel N-glycosylation sites in experiments entailing 1) flow cytometry for binding to viable cells, 2) immunohistochemistry against various human tissues, 3) ELISA against microbial Ags, and 4) protein microarrays testing reactivity against multiple autoantigens. On these grounds, N-glycosylation appears as relevant for the natural history of at least a fraction of Ig-mutated chronic lymphocytic leukemia. Moreover, subset #201 emerges as a paradigmatic case for the role of affinity maturation in the evolution of Ag reactivity of the clonotypic BCR Ig.
MeSH term(s)	Humans ; Leukemia, Lymphocytic, Chronic, B-Cell ; Receptors, Antigen, B-Cell/genetics ; Receptors, Antigen, B-Cell/metabolism ; Glycosylation ; Antigens/metabolism
Chemical Substances	Receptors, Antigen, B-Cell ; Antigens
Language	English
Publishing date	2023-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2300330
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