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Journal Articles
2024
1.
Gregoris F; Minervini G; Tosatto S C E
In Silico Exploration of AHR-HIF Pathway Interplay: Implications for Therapeutic Targeting in ccRCC Journal Article
In: Genes, vol. 15, no. 9, 2024, (Cited by: 0; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85205114282,
title = {In Silico Exploration of AHR-HIF Pathway Interplay: Implications for Therapeutic Targeting in ccRCC},
author = {Francesco Gregoris and Giovanni Minervini and Silvio C. E. Tosatto},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85205114282&origin=inward},
doi = {10.3390/genes15091167},
year = {2024},
date = {2024-01-01},
journal = {Genes},
volume = {15},
number = {9},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
abstract = {© 2024 by the authors.The oxygen-sensing pathway is a crucial regulatory circuit that defines cellular conditions and is extensively exploited in cancer development. Pathogenic mutations in the von Hippel–Lindau (VHL) tumour suppressor impair its role as a master regulator of hypoxia-inducible factors (HIFs), leading to constitutive HIF activation and uncontrolled angiogenesis, increasing the risk of developing clear cell renal cell carcinoma (ccRCC). HIF hyperactivation can sequester HIF-1β, preventing the aryl hydrocarbon receptor (AHR) from correctly activating gene expression in response to endogenous and exogenous ligands such as TCDD (dioxins). In this study, we used protein–protein interaction networks and gene expression profiling to characterize the impact of VHL loss on AHR activity. Our findings reveal specific expression patterns of AHR interactors following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in ccRCC. We identified several AHR interactors significantly associated with poor survival rates in ccRCC patients. Notably, the upregulation of the androgen receptor (AR) and retinoblastoma-associated protein (RB1) by TCDD, coupled with their respective downregulation in ccRCC and association with poor survival rates, suggests novel therapeutic targets. The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions.},
note = {Cited by: 0; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2024 by the authors.The oxygen-sensing pathway is a crucial regulatory circuit that defines cellular conditions and is extensively exploited in cancer development. Pathogenic mutations in the von Hippel–Lindau (VHL) tumour suppressor impair its role as a master regulator of hypoxia-inducible factors (HIFs), leading to constitutive HIF activation and uncontrolled angiogenesis, increasing the risk of developing clear cell renal cell carcinoma (ccRCC). HIF hyperactivation can sequester HIF-1β, preventing the aryl hydrocarbon receptor (AHR) from correctly activating gene expression in response to endogenous and exogenous ligands such as TCDD (dioxins). In this study, we used protein–protein interaction networks and gene expression profiling to characterize the impact of VHL loss on AHR activity. Our findings reveal specific expression patterns of AHR interactors following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in ccRCC. We identified several AHR interactors significantly associated with poor survival rates in ccRCC patients. Notably, the upregulation of the androgen receptor (AR) and retinoblastoma-associated protein (RB1) by TCDD, coupled with their respective downregulation in ccRCC and association with poor survival rates, suggests novel therapeutic targets. The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions.
2.
Inciardi I; Rizzotto E; Gregoris F; Fongaro B; Sosic A; Minervini G; Laureto P P
Catechol-induced covalent modifications modulate the aggregation tendency of α-synuclein: An in-solution and in-silico study Journal Article
In: BioFactors, 2024, (Cited by: 1).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85194767977,
title = {Catechol-induced covalent modifications modulate the aggregation tendency of α-synuclein: An in-solution and in-silico study},
author = {Ilenia Inciardi and Elena Rizzotto and Francesco Gregoris and Benedetta Fongaro and Alice Sosic and Giovanni Minervini and Patrizia Polverino Laureto},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85194767977&origin=inward},
doi = {10.1002/biof.2086},
year = {2024},
date = {2024-01-01},
journal = {BioFactors},
publisher = {John Wiley and Sons Inc},
abstract = {© 2024 International Union of Biochemistry and Molecular Biology.Parkinson's disease (PD) stands as a challenging neurodegenerative condition characterized by the emergence of Lewy Bodies (LBs), intracellular inclusions within dopaminergic neurons. These LBs harbor various proteins, prominently including α-Synuclein (Syn) aggregates, implicated in disease pathology. A promising avenue in PD treatment involves targeting Syn aggregation. Recent findings from our research have shown that 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET) possess the ability to impede the formation of Syn fibrils by disrupting the aggregation process. Notably, these compounds primarily engage in noncovalent interactions with the protein, leading to the formation of off-pathway oligomers that deter fibril growth. Through proteolysis studies and mass spectrometry (MS) analysis, we have identified potential covalent modifications of Syn in the presence of DOPAC, although the exact site remains elusive. Employing molecular dynamics simulations, we delved into how DOPAC-induced covalent alterations might affect the mechanism of Syn aggregation. Our findings indicate that the addition of a covalent adduct on certain residues enhances fibril flexibility without compromising its secondary structure stability. Furthermore, in the monomeric state, the modified residue fosters novel bonding interactions, thereby influencing long-range interactions between the N- and C-termini of the protein.},
note = {Cited by: 1},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2024 International Union of Biochemistry and Molecular Biology.Parkinson’s disease (PD) stands as a challenging neurodegenerative condition characterized by the emergence of Lewy Bodies (LBs), intracellular inclusions within dopaminergic neurons. These LBs harbor various proteins, prominently including α-Synuclein (Syn) aggregates, implicated in disease pathology. A promising avenue in PD treatment involves targeting Syn aggregation. Recent findings from our research have shown that 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET) possess the ability to impede the formation of Syn fibrils by disrupting the aggregation process. Notably, these compounds primarily engage in noncovalent interactions with the protein, leading to the formation of off-pathway oligomers that deter fibril growth. Through proteolysis studies and mass spectrometry (MS) analysis, we have identified potential covalent modifications of Syn in the presence of DOPAC, although the exact site remains elusive. Employing molecular dynamics simulations, we delved into how DOPAC-induced covalent alterations might affect the mechanism of Syn aggregation. Our findings indicate that the addition of a covalent adduct on certain residues enhances fibril flexibility without compromising its secondary structure stability. Furthermore, in the monomeric state, the modified residue fosters novel bonding interactions, thereby influencing long-range interactions between the N- and C-termini of the protein.
3.
Bellanda M; Damulewicz M; Zambelli B; Costanzi E; Gregoris F; Mammi S; Tosatto S C E; Costa R; Minervini G; Mazzotta G M
A PDZ scaffolding/CaM-mediated pathway in Cryptochrome signaling Journal Article
In: Protein Science, vol. 33, no. 3, 2024, (Cited by: 1).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85185346556,
title = {A PDZ scaffolding/CaM-mediated pathway in Cryptochrome signaling},
author = {Massimo Bellanda and Milena Damulewicz and Barbara Zambelli and Elisa Costanzi and Francesco Gregoris and Stefano Mammi and Silvio C. E. Tosatto and Rodolfo Costa and Giovanni Minervini and Gabriella M. Mazzotta},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85185346556&origin=inward},
doi = {10.1002/pro.4914},
year = {2024},
date = {2024-01-01},
journal = {Protein Science},
volume = {33},
number = {3},
publisher = {John Wiley and Sons Inc},
abstract = {© 2024 The Protein Society.Cryptochromes are cardinal constituents of the circadian clock, which orchestrates daily physiological rhythms in living organisms. A growing body of evidence points to their participation in pathways that have not traditionally been associated with circadian clock regulation, implying that cryptochromes may be subject to modulation by multiple signaling mechanisms. In this study, we demonstrate that human CRY2 (hCRY2) forms a complex with the large, modular scaffolding protein known as Multi-PDZ Domain Protein 1 (MUPP1). This interaction is facilitated by the calcium-binding protein Calmodulin (CaM) in a calcium-dependent manner. Our findings suggest a novel cooperative mechanism for the regulation of mammalian cryptochromes, mediated by calcium ions (Ca2+) and CaM. We propose that this Ca2+/CaM-mediated signaling pathway may be an evolutionarily conserved mechanism that has been maintained from Drosophila to mammals, most likely in relation to its potential role in the broader context of cryptochrome function and regulation. Further, the understanding of cryptochrome interactions with other proteins and signaling pathways could lead to a better definition of its role within the intricate network of molecular interactions that govern circadian rhythms.},
note = {Cited by: 1},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2024 The Protein Society.Cryptochromes are cardinal constituents of the circadian clock, which orchestrates daily physiological rhythms in living organisms. A growing body of evidence points to their participation in pathways that have not traditionally been associated with circadian clock regulation, implying that cryptochromes may be subject to modulation by multiple signaling mechanisms. In this study, we demonstrate that human CRY2 (hCRY2) forms a complex with the large, modular scaffolding protein known as Multi-PDZ Domain Protein 1 (MUPP1). This interaction is facilitated by the calcium-binding protein Calmodulin (CaM) in a calcium-dependent manner. Our findings suggest a novel cooperative mechanism for the regulation of mammalian cryptochromes, mediated by calcium ions (Ca2+) and CaM. We propose that this Ca2+/CaM-mediated signaling pathway may be an evolutionarily conserved mechanism that has been maintained from Drosophila to mammals, most likely in relation to its potential role in the broader context of cryptochrome function and regulation. Further, the understanding of cryptochrome interactions with other proteins and signaling pathways could lead to a better definition of its role within the intricate network of molecular interactions that govern circadian rhythms.
4.
Conte A D; Camagni G F; Clementel D; Minervini G; Monzon A M; Ferrari C; Piovesan D; Tosatto S C E
RING 4.0: Faster residue interaction networks with novel interaction types across over 35,000 different chemical structures Journal Article
In: Nucleic Acids Research, vol. 52, no. W1, pp. W306-W312, 2024, (Cited by: 5; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85197788039,
title = {RING 4.0: Faster residue interaction networks with novel interaction types across over 35,000 different chemical structures},
author = {Alessio Del Conte and Giorgia F Camagni and Damiano Clementel and Giovanni Minervini and Alexander Miguel Monzon and Carlo Ferrari and Damiano Piovesan and Silvio C. E Tosatto},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85197788039&origin=inward},
doi = {10.1093/nar/gkae337},
year = {2024},
date = {2024-01-01},
journal = {Nucleic Acids Research},
volume = {52},
number = {W1},
pages = {W306-W312},
publisher = {Oxford University Press},
abstract = {© 2024 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.Residue interaction networks (RINs) are a valuable approach for representing contacts in protein structures. RINs have been widely used in various research areas, including the analysis of mutation effects, domain-domain communication, catalytic activity, and molecular dynamics simulations. The RING server is a powerful tool to calculate non-covalent molecular interactions based on geometrical parameters, providing high-quality and reliable results. Here, we introduce RING 4.0, which includes significant enhancements for identifying both covalent and non-covalent bonds in protein structures. It now encompasses seven different interaction types, with the addition of π-hydrogen, halogen bonds and metal ion coordination sites. The definitions of all available bond types have also been refined and RING can now process the complete PDB chemical component dictionary (over 35000 different molecules) which provides atom names and covalent connectivity information for all known ligands. Optimization of the software has improved execution time by an order of magnitude. The RING web server has been redesigned to provide a more engaging and interactive user experience, incorporating new visualization tools. Users can now visualize all types of interactions simultaneously in the structure viewer and network component. The web server, including extensive help and tutorials, is available from URL: https://ring.biocomputingup.it/.},
note = {Cited by: 5; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2024 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.Residue interaction networks (RINs) are a valuable approach for representing contacts in protein structures. RINs have been widely used in various research areas, including the analysis of mutation effects, domain-domain communication, catalytic activity, and molecular dynamics simulations. The RING server is a powerful tool to calculate non-covalent molecular interactions based on geometrical parameters, providing high-quality and reliable results. Here, we introduce RING 4.0, which includes significant enhancements for identifying both covalent and non-covalent bonds in protein structures. It now encompasses seven different interaction types, with the addition of π-hydrogen, halogen bonds and metal ion coordination sites. The definitions of all available bond types have also been refined and RING can now process the complete PDB chemical component dictionary (over 35000 different molecules) which provides atom names and covalent connectivity information for all known ligands. Optimization of the software has improved execution time by an order of magnitude. The RING web server has been redesigned to provide a more engaging and interactive user experience, incorporating new visualization tools. Users can now visualize all types of interactions simultaneously in the structure viewer and network component. The web server, including extensive help and tutorials, is available from URL: https://ring.biocomputingup.it/.
2023
5.
Conte A D; Monzon A M; Clementel D; Camagni G F; Minervini G; Tosatto S C E; Piovesan D
RING-PyMOL: residue interaction networks of structural ensembles and molecular dynamics Journal Article
In: Bioinformatics, vol. 39, no. 5, 2023, (Cited by: 8; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85159553803,
title = {RING-PyMOL: residue interaction networks of structural ensembles and molecular dynamics},
author = {Alessio Del Conte and Alexander Miguel Monzon and Damiano Clementel and Giorgia F. Camagni and Giovanni Minervini and Silvio C. E. Tosatto and Damiano Piovesan},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85159553803&origin=inward},
doi = {10.1093/bioinformatics/btad260},
year = {2023},
date = {2023-01-01},
journal = {Bioinformatics},
volume = {39},
number = {5},
publisher = {Oxford University Press},
abstract = {© The Author(s) 2023. Published by Oxford University Press.RING-PyMOL is a plugin for PyMOL providing a set of analysis tools for structural ensembles and molecular dynamic simulations. RING-PyMOL combines residue interaction networks, as provided by the RING software, with structural clustering to enhance the analysis and visualization of the conformational complexity. It combines precise calculation of non-covalent interactions with the power of PyMOL to manipulate and visualize protein structures. The plugin identifies and highlights correlating contacts and interaction patterns that can explain structural allostery, active sites, and structural heterogeneity connected with molecular function. It is easy to use and extremely fast, processing and rendering hundreds of models and long trajectories in seconds. RING-PyMOL generates a number of interactive plots and output files for use with external tools. The underlying RING software has been improved extensively. It is 10 times faster, can process mmCIF files and it identifies typed interactions also for nucleic acids.},
note = {Cited by: 8; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© The Author(s) 2023. Published by Oxford University Press.RING-PyMOL is a plugin for PyMOL providing a set of analysis tools for structural ensembles and molecular dynamic simulations. RING-PyMOL combines residue interaction networks, as provided by the RING software, with structural clustering to enhance the analysis and visualization of the conformational complexity. It combines precise calculation of non-covalent interactions with the power of PyMOL to manipulate and visualize protein structures. The plugin identifies and highlights correlating contacts and interaction patterns that can explain structural allostery, active sites, and structural heterogeneity connected with molecular function. It is easy to use and extremely fast, processing and rendering hundreds of models and long trajectories in seconds. RING-PyMOL generates a number of interactive plots and output files for use with external tools. The underlying RING software has been improved extensively. It is 10 times faster, can process mmCIF files and it identifies typed interactions also for nucleic acids.
6.
Camagni G F; Minervini G; Tosatto S C E
Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations Journal Article
In: International Journal of Molecular Sciences, vol. 24, no. 5, 2023, (Cited by: 3; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85149881431,
title = {Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations},
author = {Giorgia F. Camagni and Giovanni Minervini and Silvio C. E. Tosatto},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85149881431&origin=inward},
doi = {10.3390/ijms24054710},
year = {2023},
date = {2023-01-01},
journal = {International Journal of Molecular Sciences},
volume = {24},
number = {5},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
abstract = {© 2023 by the authors.The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD’s activity.},
note = {Cited by: 3; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2023 by the authors.The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD’s activity.
7.
Piol D; Tosatto L; Zuccaro E; Anderson E N; Falconieri A; Polanco M J; Marchioretti C; Lia F; White J; Bregolin E; Minervini G; Parodi S; Salvatella X; Arrigoni G; Ballabio A; Spada A R L; Tosatto S C E; Sambataro F; Medina D L; Pandey U B; Basso M; Pennuto M
Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function Journal Article
In: Science Advances, vol. 9, no. 1, 2023, (Cited by: 6; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85145870213,
title = {Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function},
author = {Diana Piol and Laura Tosatto and Emanuela Zuccaro and Eric N. Anderson and Antonella Falconieri and Maria J. Polanco and Caterina Marchioretti and Federica Lia and Joseph White and Elisa Bregolin and Giovanni Minervini and Sara Parodi and Xavier Salvatella and Giorgio Arrigoni and Andrea Ballabio and Albert R. La Spada and Silvio C. E. Tosatto and Fabio Sambataro and Diego L. Medina and Udai B. Pandey and Manuela Basso and Maria Pennuto},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85145870213&origin=inward},
doi = {10.1126/sciadv.ade1694},
year = {2023},
date = {2023-01-01},
journal = {Science Advances},
volume = {9},
number = {1},
publisher = {American Association for the Advancement of Science},
abstract = {Copyright © 2023 The Authors, some rights reserved;Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR function and toxicity in cells, flies, and mice. Ablation of CDK2 reduced AR phosphorylation in the brainstem and restored expression of Myc and other genes involved in DNA damage, senescence, and apoptosis, indicating that the cell cycle–regulated kinase plays more than a bystander role in SBMA-vulnerable postmitotic cells.},
note = {Cited by: 6; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Copyright © 2023 The Authors, some rights reserved;Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR function and toxicity in cells, flies, and mice. Ablation of CDK2 reduced AR phosphorylation in the brainstem and restored expression of Myc and other genes involved in DNA damage, senescence, and apoptosis, indicating that the cell cycle–regulated kinase plays more than a bystander role in SBMA-vulnerable postmitotic cells.
8.
Rocca M S; Minervini G; Vinanzi C; Bottacin A; Lia F; Foresta C; Pennuto M; Ferlin A
Mutational Screening of Androgen Receptor Gene in 8224 Men of Infertile Couples Journal Article
In: Journal of Clinical Endocrinology and Metabolism, vol. 108, no. 5, pp. 1181-1191, 2023, (Cited by: 2; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85152486041,
title = {Mutational Screening of Androgen Receptor Gene in 8224 Men of Infertile Couples},
author = {Maria Santa Rocca and Giovanni Minervini and Cinzia Vinanzi and Alberto Bottacin and Federica Lia and Carlo Foresta and Maria Pennuto and Alberto Ferlin},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85152486041&origin=inward},
doi = {10.1210/clinem/dgac671},
year = {2023},
date = {2023-01-01},
journal = {Journal of Clinical Endocrinology and Metabolism},
volume = {108},
number = {5},
pages = {1181-1191},
publisher = {Endocrine Society},
abstract = {© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.Context: Mutations in the androgen receptor (AR) gene might be associated with infertility mainly because they cause various degrees of androgen insensitivity. Objective: The aim of the study was to evaluate the frequency and type of AR variants in a large cohort of infertile males. Methods: A total of 8224 males of Italian idiopathic infertile couples were referred to the University Hospital of Padova. The main outcome measures were mutational screening of AR, computational, and functional analyses. Results: We found 131 patients (1.6%) harboring 45 variants in AR gene, of which 18 were novel missense AR variants. Patients with AR gene variants had lower sperm count (P = .048), higher testosterone (T) concentration (P < .0001), and higher androgen sensitivity index (ASI) (luteinizing hormone × T, P < .001) than patients without variants. Statistical analyses found T ≥ 15.38 nmol/L and ASI ≥ 180 IU × nmol/L2 as the threshold values to discriminate with good accuracy patients with AR variants. Patients with oligozoospermia and T ≥ 15.38 nmol/L had a 9-fold increased risk of harboring mutations compared with patients with normal sperm count and T < 15.38 nmol/L (odds ratio 9.29, 95% CI 5.07-17.02). Using computational and functional approaches, we identified 2 novel variants, L595P and L791I, as potentially pathogenic. Conclusion: This is the largest study screening AR gene variants in men of idiopathic infertile couples. We found that the prevalence of variants increased to 3.4% in oligozoospermic subjects with T ≥ 15.38 nmol/L. Conversely, more than 80% of men with AR gene variants had low sperm count and high T levels. Based on our findings, we suggest AR sequencing as a routine genetic test in cases of idiopathic oligozoospermia with T ≥ 15.38 nmol/L.},
note = {Cited by: 2; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.Context: Mutations in the androgen receptor (AR) gene might be associated with infertility mainly because they cause various degrees of androgen insensitivity. Objective: The aim of the study was to evaluate the frequency and type of AR variants in a large cohort of infertile males. Methods: A total of 8224 males of Italian idiopathic infertile couples were referred to the University Hospital of Padova. The main outcome measures were mutational screening of AR, computational, and functional analyses. Results: We found 131 patients (1.6%) harboring 45 variants in AR gene, of which 18 were novel missense AR variants. Patients with AR gene variants had lower sperm count (P = .048), higher testosterone (T) concentration (P < .0001), and higher androgen sensitivity index (ASI) (luteinizing hormone × T, P < .001) than patients without variants. Statistical analyses found T ≥ 15.38 nmol/L and ASI ≥ 180 IU × nmol/L2 as the threshold values to discriminate with good accuracy patients with AR variants. Patients with oligozoospermia and T ≥ 15.38 nmol/L had a 9-fold increased risk of harboring mutations compared with patients with normal sperm count and T < 15.38 nmol/L (odds ratio 9.29, 95% CI 5.07-17.02). Using computational and functional approaches, we identified 2 novel variants, L595P and L791I, as potentially pathogenic. Conclusion: This is the largest study screening AR gene variants in men of idiopathic infertile couples. We found that the prevalence of variants increased to 3.4% in oligozoospermic subjects with T ≥ 15.38 nmol/L. Conversely, more than 80% of men with AR gene variants had low sperm count and high T levels. Based on our findings, we suggest AR sequencing as a routine genetic test in cases of idiopathic oligozoospermia with T ≥ 15.38 nmol/L.
2022
9.
Falconieri A; Minervini G; Quaglia F; Sartori G; Tosatto S C E
Characterization of the pVHL Interactome in Human Testis Using High-Throughput Library Screening Journal Article
In: Cancers, vol. 14, no. 4, 2022, (Cited by: 1; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85124955220,
title = {Characterization of the pVHL Interactome in Human Testis Using High-Throughput Library Screening},
author = {Antonella Falconieri and Giovanni Minervini and Federica Quaglia and Geppo Sartori and Silvio C. E. Tosatto},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85124955220&origin=inward},
doi = {10.3390/cancers14041009},
year = {2022},
date = {2022-01-01},
journal = {Cancers},
volume = {14},
number = {4},
publisher = {MDPI},
abstract = {© 2022 by the authors. Licensee MDPI, Basel, Switzerland.Functional impairment of the von Hippel–Lindau tumor suppressor (pVHL) is causative of a familiar increased risk of developing cancer. As an E3 substrate recognition particle, pVHL marks the hypoxia inducible factor 1α (HIF-1α) for degradation in normoxic conditions, thus acting as a key regulator of both acute and chronic cell adaptation to hypoxia. The male mice model carrying VHL gene conditional knockout presents significant abnormalities in testis development paired with defects in spermatogenesis and infertility, indicating that pVHL exerts testis-specific roles. Here we aimed to explore whether pVHL could have a similar role in humans by performing a testis-tissue library screening complemented with in-depth bioinformatics analysis. We identified 55 novel pVHL binding proteins directly involved in spermatogenesis, cell differentiation and reproductive metabolism. In addition, computational investigation of these new interactors identified multiple pVHL-specific binding motifs and demonstrated that somatic mutations described in human cancers reside in these binding regions. Collectively, these findings suggest that, in addition to its role in cancer formation, pVHL may also be pivotal in normal gonadal development in humans.},
note = {Cited by: 1; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.Functional impairment of the von Hippel–Lindau tumor suppressor (pVHL) is causative of a familiar increased risk of developing cancer. As an E3 substrate recognition particle, pVHL marks the hypoxia inducible factor 1α (HIF-1α) for degradation in normoxic conditions, thus acting as a key regulator of both acute and chronic cell adaptation to hypoxia. The male mice model carrying VHL gene conditional knockout presents significant abnormalities in testis development paired with defects in spermatogenesis and infertility, indicating that pVHL exerts testis-specific roles. Here we aimed to explore whether pVHL could have a similar role in humans by performing a testis-tissue library screening complemented with in-depth bioinformatics analysis. We identified 55 novel pVHL binding proteins directly involved in spermatogenesis, cell differentiation and reproductive metabolism. In addition, computational investigation of these new interactors identified multiple pVHL-specific binding motifs and demonstrated that somatic mutations described in human cancers reside in these binding regions. Collectively, these findings suggest that, in addition to its role in cancer formation, pVHL may also be pivotal in normal gonadal development in humans.
10.
Quaglia F; Salladini E; Carraro M; Minervini G; Tosatto S C E; Mercier P L
SARS-CoV-2 variants preferentially emerge at intrinsically disordered protein sites helping immune evasion Journal Article
In: FEBS Journal, vol. 289, no. 14, pp. 4240-4250, 2022, (Cited by: 22; Open Access).
Abstract | Altmetric | Dimensions | PlumX | Links:
@article{SCOPUS_ID:85124603120,
title = {SARS-CoV-2 variants preferentially emerge at intrinsically disordered protein sites helping immune evasion},
author = {Federica Quaglia and Edoardo Salladini and Marco Carraro and Giovanni Minervini and Silvio C. E. Tosatto and Philippe Le Mercier},
url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85124603120&origin=inward},
doi = {10.1111/febs.16379},
year = {2022},
date = {2022-01-01},
journal = {FEBS Journal},
volume = {289},
number = {14},
pages = {4240-4250},
publisher = {John Wiley and Sons Inc},
abstract = {© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.The SARS-CoV-2 pandemic is maintained by the emergence of successive variants, highlighting the flexibility of the protein sequences of the virus. We show that experimentally determined intrinsically disordered regions (IDRs) are abundant in the SARS-CoV-2 viral proteins, making up to 28% of disorder content for the S1 subunit of spike and up to 51% for the nucleoprotein, with the vast majority of mutations occurring in the 13 major variants mapped to these IDRs. Strikingly, antigenic sites are enriched in IDRs, in the receptor-binding domain (RBD) and in the N-terminal domain (NTD), suggesting a key role of structural flexibility in the antigenicity of the SARS-CoV-2 protein surface. Mutations occurring in the S1 subunit and nucleoprotein (N) IDRs are critical for immune evasion and antibody escape, suggesting potential additional implications for vaccines and monoclonal therapeutic strategies. Overall, this suggests the presence of variable regions on S1 and N protein surfaces, which confer sequence and antigenic flexibility to the virus without altering its protein functions.},
note = {Cited by: 22; Open Access},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.The SARS-CoV-2 pandemic is maintained by the emergence of successive variants, highlighting the flexibility of the protein sequences of the virus. We show that experimentally determined intrinsically disordered regions (IDRs) are abundant in the SARS-CoV-2 viral proteins, making up to 28% of disorder content for the S1 subunit of spike and up to 51% for the nucleoprotein, with the vast majority of mutations occurring in the 13 major variants mapped to these IDRs. Strikingly, antigenic sites are enriched in IDRs, in the receptor-binding domain (RBD) and in the N-terminal domain (NTD), suggesting a key role of structural flexibility in the antigenicity of the SARS-CoV-2 protein surface. Mutations occurring in the S1 subunit and nucleoprotein (N) IDRs are critical for immune evasion and antibody escape, suggesting potential additional implications for vaccines and monoclonal therapeutic strategies. Overall, this suggests the presence of variable regions on S1 and N protein surfaces, which confer sequence and antigenic flexibility to the virus without altering its protein functions.