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Article ; Online: Biomarkers for diagnosis and prognostication of acute aortic syndromes.

Morello, Fulvio / Nazerian, Peiman / Lupia, Enrico / Castelli, Matteo / Mills, Nicholas L / Mueller, Christian

European heart journal. Acute cardiovascular care

2024 Volume 13, Issue 2, Page(s) 254–256

MeSH term(s)	Humans ; Biomarkers ; Aortic Dissection ; Acute Aortic Syndrome ; Acute Disease ; Aortic Diseases/diagnosis
Chemical Substances	Biomarkers
Language	English
Publishing date	2024-01-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2663340-1
ISSN	2048-8734 ; 2048-8726
ISSN (online)	2048-8734
ISSN	2048-8726
DOI	10.1093/ehjacc/zuae011
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Article ; Online: Acute aortic syndromes: An internist's guide to the galaxy.

Morello, Fulvio / Bima, Paolo / Castelli, Matteo / Nazerian, Peiman

European journal of internal medicine

2022 Volume 106, Page(s) 45–53

Abstract: Acute aortic syndromes (AASs) are severe conditions defined by dissection, hemorrhage, ulceration or rupture of the thoracic aorta. AASs share etiological and pathophysiological features, including long-term aortic tissue degeneration and mechanisms of ... ...

Abstract	Acute aortic syndromes (AASs) are severe conditions defined by dissection, hemorrhage, ulceration or rupture of the thoracic aorta. AASs share etiological and pathophysiological features, including long-term aortic tissue degeneration and mechanisms of acute aortic damage. The clinical signs and symptoms of AASs are unspecific and heterogeneous, requiring large differential diagnosis. When evaluating a patient with AAS-compatible symptoms, physicians need to integrate clinical probability assessment, bedside imaging techniques such as point-of-care ultrasound, and blood test results such as d-dimer. The natural history of AASs is dominated by engagement of ischemic, coagulative and inflammatory pathways at large, causing multiorgan damage. Medical treatment, multiorgan monitoring and outcome prognostication are therefore paramount, with internal medicine playing a key role in non-surgical management of AASs.
MeSH term(s)	Humans ; Aneurysm, Dissecting/diagnostic imaging ; Aneurysm, Dissecting/therapy ; Syndrome ; Aorta, Thoracic ; Diagnosis, Differential
Language	English
Publishing date	2022-10-11
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1038679-8
ISSN	1879-0828 ; 0953-6205
ISSN (online)	1879-0828
ISSN	0953-6205
DOI	10.1016/j.ejim.2022.10.003
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Zs.A 2608: Show issues

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Article ; Online: Studying the Dynamics of a Complex G-Quadruplex System: Insights into the Comparison of MD and NMR Data.

Castelli, Matteo / Doria, Filippo / Freccero, Mauro / Colombo, Giorgio / Moroni, Elisabetta

Journal of chemical theory and computation

2022 Volume 18, Issue 7, Page(s) 4515–4528

Abstract: Molecular dynamics (MD) simulations are coming of age in the study of nucleic acids, including specific tertiary structures such as G-quadruplexes. While being precious for providing structural and dynamic information inaccessible to experiments at the ... ...

Abstract	Molecular dynamics (MD) simulations are coming of age in the study of nucleic acids, including specific tertiary structures such as G-quadruplexes. While being precious for providing structural and dynamic information inaccessible to experiments at the atomistic level of resolution, MD simulations in this field may still be limited by several factors. These include the force fields used, different models for ion parameters, ionic strengths, and water models. We address various aspects of this problem by analyzing and comparing microsecond-long atomistic simulations of the G-quadruplex structure formed by the human immunodeficiency virus long terminal repeat (HIV LTR)-III sequence for which nuclear magnetic resonance (NMR) structures are available. The system is studied in different conditions, systematically varying the ionic strengths, ion numbers, and water models. We comparatively analyze the dynamic behavior of the G-quadruplex motif in various conditions and assess the ability of each simulation to satisfy the nuclear magnetic resonance (NMR)-derived experimental constraints and structural parameters. The conditions taking into account K
MeSH term(s)	G-Quadruplexes ; HIV Infections ; Humans ; Ions/chemistry ; Magnetic Resonance Spectroscopy ; Molecular Dynamics Simulation ; Nucleic Acid Conformation ; Water/chemistry
Chemical Substances	Ions ; Water (059QF0KO0R)
Language	English
Publishing date	2022-06-06
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/acs.jctc.2c00291
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Article ; Online: Phosphorylation of the Hsp90 Co-Chaperone Hop Changes its Conformational Dynamics and Biological Function.

Castelli, Matteo / Bhattacharya, Kaushik / Abboud, Ernest / Serapian, Stefano A / Picard, Didier / Colombo, Giorgio

Journal of molecular biology

2022 Volume 435, Issue 3, Page(s) 167931

Abstract: The molecular chaperones Hsp90 and Hsp70 and their regulatory co-chaperone Hop play a key role at the crossroads of the folding pathways of numerous client proteins by forming fine-tuned multiprotein complexes. Alterations of the biomolecules involved ... ...

Abstract	The molecular chaperones Hsp90 and Hsp70 and their regulatory co-chaperone Hop play a key role at the crossroads of the folding pathways of numerous client proteins by forming fine-tuned multiprotein complexes. Alterations of the biomolecules involved may functionally impact the chaperone machinery: here, we integrate simulations and experiments to unveil how Hop conformational fitness and interactions can be controlled by the perturbation of just one residue. Specifically, we unveil how mechanisms mediated by Hop residue Y354 control Hop open and closed states, which affect binding of Hsp70/Hsp90. Phosphorylation or mutation of Hop-Y354 are shown to favor structural ensembles that are indeed not optimal for stable interactions with Hsp90 and Hsp70. This disfavors cellular accumulation of the stringent Hsp90 clients glucocorticoid receptor and the viral tyrosine kinase v-Src, with detrimental effects on v-Src activity. Our results show how the post-translational modification of a specific residue in Hop provides a regulation mechanism for the larger chaperone complex of which it is part. In this framework, the effects of one single alteration are amplified at the cellular level through the perturbation of protein-interaction networks.
MeSH term(s)	Humans ; Phosphorylation ; Molecular Chaperones/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Protein-Tyrosine Kinases/metabolism ; Protein Binding
Chemical Substances	Molecular Chaperones ; HSP90 Heat-Shock Proteins ; HSP70 Heat-Shock Proteins ; Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2022-12-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2022.167931
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Zs.A 867: Show issues

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Article: AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity.

Perna, Laura / Castelli, Matteo / Frasnetti, Elena / Romano, Lisa E L / Colombo, Giorgio / Prodromou, Chrisostomos / Chapple, J Paul

Frontiers in molecular biosciences

2023 Volume 9, Page(s) 1074714

Abstract: The ataxia-linked protein sacsin has three regions of partial homology to Hsp90's N-terminal ATP binding domain. Although a crystal structure for this Hsp90-like domain has been reported the precise molecular interactions required for ATP-binding and ... ...

Abstract	The ataxia-linked protein sacsin has three regions of partial homology to Hsp90's N-terminal ATP binding domain. Although a crystal structure for this Hsp90-like domain has been reported the precise molecular interactions required for ATP-binding and hydrolysis are unclear and it is debatable whether ATP biding is compatible with these domains. Furthermore, the Identification of a sacsin domain(s) equivalent to the middle domain of Hsp90 has been elusive. Here we present the superimposition of an AlphaFold structure of sacsin with yeast Hsp90, which provides novel insights into sacsin's structure. We identify residues within the sacsin Hsp90-like domains that are required for ATP binding and hydrolysis, including the putative catalytic arginine residues equivalent to that of the Hsp90 middle domain. Importantly, our analysis allows comparison of the Hsp90 middle domain with corresponding sacsin regions and identifies a shorter lid segment, in the sacsin ATP-binding domains, than the one found in the N-terminal domain of Hsp90. Our results show how a realignment of residues in the lid segment of sacsin that are involved in ATP binding can better match equivalent residues seen in Hsp90, which we then corroborated using molecular dynamic simulations. We speculate, from a structural viewpoint, why some ATP competitive inhibitors of Hsp90 may not bind sacsin, while others would. Together our analysis supports the hypothesis that sacsin's function is ATP-driven and would be consistent with it having a role as a super molecular chaperone. We propose that the SR1 regions of sacsin be renamed as HSP-NRD (Hsp90 N-Terminal Repeat Domain; residues 84-324) and the fragment immediately after as HSP-MRD (Hsp90 Middle Repeat Domain; residues 325-518).
Language	English
Publishing date	2023-01-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2022.1074714
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Article ; Online: Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary

Castelli, Matteo / Marchetti, Filippo / Osuna, Sílvia / F Oliveira, A Sofia / Mulholland, Adrian J / Serapian, Stefano A / Colombo, Giorgio

Journal of the American Chemical Society

2023 Volume 146, Issue 1, Page(s) 901–919

Abstract: Protein functions are dynamically regulated by allostery, which enables conformational communication even between faraway residues, and expresses itself in many forms, akin to different "languages": allosteric control pathways predominating in an ... ...

Abstract	Protein functions are dynamically regulated by allostery, which enables conformational communication even between faraway residues, and expresses itself in many forms, akin to different "languages": allosteric control pathways predominating in an unperturbed protein are often unintuitively reshaped whenever biochemical perturbations arise (
MeSH term(s)	Molecular Dynamics Simulation ; Proteins/chemistry ; Catalytic Domain ; Guanosine Triphosphate/metabolism ; Allosteric Regulation
Chemical Substances	Proteins ; Guanosine Triphosphate (86-01-1)
Language	English
Publishing date	2023-12-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.3c11396
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Article ; Online: Molecular mechanisms of chaperone-directed protein folding: Insights from atomistic simulations.

Castelli, Matteo / Magni, Andrea / Bonollo, Giorgio / Pavoni, Silvia / Frigerio, Francesco / Oliveira, A Sofia F / Cinquini, Fabrizio / Serapian, Stefano A / Colombo, Giorgio

Protein science : a publication of the Protein Society

2023 Volume 33, Issue 3, Page(s) e4880

Abstract: Molecular chaperones, a family of proteins of which Hsp90 and Hsp70 are integral members, form an essential machinery to maintain healthy proteomes by controlling the folding and activation of a plethora of substrate client proteins. This is achieved ... ...

Abstract	Molecular chaperones, a family of proteins of which Hsp90 and Hsp70 are integral members, form an essential machinery to maintain healthy proteomes by controlling the folding and activation of a plethora of substrate client proteins. This is achieved through cycles in which Hsp90 and Hsp70, regulated by task-specific co-chaperones, process ATP and become part of a complex network that undergoes extensive compositional and conformational variations. Despite impressive advances in structural knowledge, the mechanisms that regulate the dynamics of functional assemblies, their response to nucleotides, and their relevance for client remodeling are still elusive. Here, we focus on the glucocorticoid receptor (GR):Hsp90:Hsp70:co-chaperone Hop client-loading and the GR:Hsp90:co-chaperone p23 client-maturation complexes, key assemblies in the folding cycle of glucocorticoid receptor (GR), a client strictly dependent upon Hsp90/Hsp70 for activity. Using a combination of molecular dynamics simulation approaches, we unveil with unprecedented detail the mechanisms that underpin function in these chaperone machineries. Specifically, we dissect the processes by which the nucleotide-encoded message is relayed to the client and how the distinct partners of the assemblies cooperate to (pre)organize partially folded GR during Loading and Maturation. We show how different ligand states determine distinct dynamic profiles for the functional interfaces defining the interactions in the complexes and modulate their overall flexibility to facilitate progress along the chaperone cycle. Finally, we also show that the GR regions engaged by the chaperone machinery display peculiar energetic signatures in the folded state, which enhance the probability of partial unfolding fluctuations. From these results, we propose a model where a dynamic cross-talk emerges between the chaperone dynamics states and remodeling of client-interacting regions. This factor, coupled to the highly dynamic nature of the assemblies and the conformational heterogeneity of their interactions, provides the basis for regulating the functions of distinct assemblies during the chaperoning cycle.
Language	English
Publishing date	2023-12-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4880
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: NLRP3 monomer functional dynamics: From the effects of allosteric binding to implications for drug design.

Casali, Emanuele / Serapian, Stefano A / Gianquinto, Eleonora / Castelli, Matteo / Bertinaria, Massimo / Spyrakis, Francesca / Colombo, Giorgio

International journal of biological macromolecules

2023 Volume 246, Page(s) 125609

Abstract: The protein NLRP3 and its complexes are associated with an array of inflammatory pathologies, among which neurodegenerative, autoimmune, and metabolic diseases. Targeting the NLRP3 inflammasome represents a promising strategy for easing the symptoms of ... ...

Abstract	The protein NLRP3 and its complexes are associated with an array of inflammatory pathologies, among which neurodegenerative, autoimmune, and metabolic diseases. Targeting the NLRP3 inflammasome represents a promising strategy for easing the symptoms of pathologic neuroinflammation. When the inflammasome is activated, NLRP3 undergoes a conformational change triggering the production of pro-inflammatory cytokines IL-1β and IL-18, as well as cell death by pyroptosis. NLRP3 nucleotide-binding and oligomerization (NACHT) domain plays a crucial role in this function by binding and hydrolysing ATP and is primarily responsible, together with conformational transitions involving the PYD domain, for the complex-assembly process. Allosteric ligands proved able to induce NLRP3 inhibition. Herein, we examine the origins of allosteric inhibition of NLRP3. Through the use of molecular dynamics (MD) simulations and advanced analysis methods, we provide molecular-level insights into how allosteric binding affects protein structure and dynamics, remodelling of the conformational ensembles populated by the protein, with key reverberations on how NLRP3 is preorganized for assembly and ultimately function. The data are used to develop a Machine Learning model to define the protein as Active or Inactive, only based on the analysis of its internal dynamics. We propose this model as a novel tool to select allosteric ligands.
MeSH term(s)	Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Ligands ; Cytokines ; Drug Design ; Interleukin-1beta/metabolism
Chemical Substances	Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; Ligands ; Cytokines ; Interleukin-1beta
Language	English
Publishing date	2023-07-01
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	282732-3
ISSN	1879-0003 ; 0141-8130
ISSN (online)	1879-0003
ISSN	0141-8130
DOI	10.1016/j.ijbiomac.2023.125609
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Article ; Online: Pre-Test Probability Assessment and d-Dimer Based Evaluation in Patients with Previous Acute Aortic Syndrome.

Morello, Fulvio / Santoro, Marco / Giachino, Francesca / Caciolli, Francesca / Capretti, Elisa / Castelli, Matteo / Pivetta, Emanuele / Nazerian, Peiman / Lupia, Enrico

Medicina (Kaunas, Lithuania)

2023 Volume 59, Issue 3

Abstract: Background and ... ...

Abstract	Background and Objectives
MeSH term(s)	Humans ; Acute Aortic Syndrome ; Aortic Dissection/diagnosis ; Probability ; Pain ; Biomarkers
Chemical Substances	fibrin fragment D ; Biomarkers
Language	English
Publishing date	2023-03-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2188113-3
ISSN	1648-9144 ; 1010-660X
ISSN (online)	1648-9144
ISSN	1010-660X
DOI	10.3390/medicina59030548
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Article ; Online: How aberrant N-glycosylation can alter protein functionality and ligand binding: An atomistic view.

Castelli, Matteo / Yan, Pengrong / Rodina, Anna / Digwal, Chander S / Panchal, Palak / Chiosis, Gabriela / Moroni, Elisabetta / Colombo, Giorgio

Structure (London, England : 1993)

2023 Volume 31, Issue 8, Page(s) 987–1004.e8

Abstract: Protein-assembly defects due to an enrichment of aberrant conformational protein variants are emerging as a new frontier in therapeutics design. Understanding the structural elements that rewire the conformational dynamics of proteins and pathologically ... ...

Abstract	Protein-assembly defects due to an enrichment of aberrant conformational protein variants are emerging as a new frontier in therapeutics design. Understanding the structural elements that rewire the conformational dynamics of proteins and pathologically perturb functionally oriented ensembles is important for inhibitor development. Chaperones are hub proteins for the assembly of multiprotein complexes and an enrichment of aberrant conformers can affect the cellular proteome, and in turn, phenotypes. Here, we integrate computational and experimental tools to investigte how N-glycosylation of specific residues in glucose-regulated protein 94 (GRP94) modulates internal dynamics and alters the conformational fitness of regions fundamental for the interaction with ATP and synthetic ligands and impacts substructures important for the recognition of interacting proteins. N-glycosylation plays an active role in modulating the energy landscape of GRP94, and we provide support for leveraging the knowledge on distinct glycosylation variants to design molecules targeting GRP94 disease-associated conformational states and assemblies.
MeSH term(s)	Glycosylation ; Ligands ; Molecular Chaperones/chemistry ; Protein Conformation ; Protein Binding
Chemical Substances	Ligands ; Molecular Chaperones
Language	English
Publishing date	2023-06-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2023.05.017
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