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Article ; Online: Resistance is futile with fourth-generation EGFR inhibitors.

Marasco, Michelangelo / Misale, Sandra

Nature cancer

2024 Volume 3, Issue 4, Page(s) 381–383

MeSH term(s)	Carcinoma, Non-Small-Cell Lung ; ErbB Receptors/genetics ; Humans ; Lung Neoplasms
Chemical Substances	EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2024-02-06
Publishing country	England
Document type	Journal Article ; Comment
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-022-00365-2
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Article: Phosphopeptide binding to the N-SH2 domain of tyrosine phosphatase SHP2 correlates with the unzipping of its central β-sheet.

Marasco, Michelangelo / Kirkpatrick, John / Carlomagno, Teresa / Hub, Jochen S / Anselmi, Massimiliano

Computational and structural biotechnology journal

2024 Volume 23, Page(s) 1169–1180

Abstract: SHP2 is a tyrosine phosphatase that plays a regulatory role in multiple intracellular signaling cascades and is known to be oncogenic in certain contexts. In the absence of effectors, SHP2 adopts an autoinhibited conformation with its N-SH2 domain ... ...

Abstract	SHP2 is a tyrosine phosphatase that plays a regulatory role in multiple intracellular signaling cascades and is known to be oncogenic in certain contexts. In the absence of effectors, SHP2 adopts an autoinhibited conformation with its N-SH2 domain blocking the active site. Given the key role of N-SH2 in regulating SHP2, this domain has been extensively studied, often by X-ray crystallography. Using a combination of structural analyses and molecular dynamics (MD) simulations we show that the crystallographic environment can significantly influence the structure of the isolated N-SH2 domain, resulting in misleading interpretations. As an orthogonal method to X-ray crystallography, we use a combination of NMR spectroscopy and MD simulations to accurately determine the conformation of apo N-SH2 in solution. In contrast to earlier reports based on crystallographic data, our results indicate that apo N-SH2 in solution primarily adopts a conformation with a fully zipped central β-sheet, and that partial unzipping of this β-sheet is promoted by binding of either phosphopeptides or even phosphate/sulfate ions.
Language	English
Publishing date	2024-03-02
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2024.02.023
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Article ; Online: NMR Methods to Study the Dynamics of SH2 Domain-Phosphopeptide Complexes.

Marasco, Michelangelo / Kirkpatrick, John P / Nanna, Vittoria / Carlomagno, Teresa

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2705, Page(s) 25–37

Abstract: Nuclear magnetic resonance (NMR) spectroscopy is the method of choice for studying the dynamics of biological macromolecules in solution. By exploiting the intricate interplay between the effects of protein motion (both overall rotational diffusion and ... ...

Abstract	Nuclear magnetic resonance (NMR) spectroscopy is the method of choice for studying the dynamics of biological macromolecules in solution. By exploiting the intricate interplay between the effects of protein motion (both overall rotational diffusion and internal mobility) and nuclear spin relaxation, NMR allows molecular motion to be probed at atomic resolution over a wide range of timescales, including picosecond (bond vibrations and methyl-group rotations), nanosecond (loop motions and rotational diffusion), and microsecond-millisecond (ligand binding, allostery). In this chapter, we describe different NMR pulse schemes (R
MeSH term(s)	Phosphopeptides ; src Homology Domains ; Magnetic Resonance Imaging ; Diffusion ; Magnetic Resonance Spectroscopy
Chemical Substances	Phosphopeptides
Language	English
Publishing date	2023-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3393-9_2
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Article ; Online: Methods for Structure Determination of SH2 Domain-Phosphopeptide Complexes by NMR.

Nanna, Vittoria / Marasco, Michelangelo / Kirkpatrick, John P / Carlomagno, Teresa

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2705, Page(s) 3–23

Abstract: Nuclear magnetic resonance (NMR) spectroscopy is a powerful technique to solve the structure of biomolecular complexes at atomic resolution in solution. Small proteins such as Src-homology 2 (SH2) domains have fast tumbling rates and long-lived NMR ... ...

Abstract	Nuclear magnetic resonance (NMR) spectroscopy is a powerful technique to solve the structure of biomolecular complexes at atomic resolution in solution. Small proteins such as Src-homology 2 (SH2) domains have fast tumbling rates and long-lived NMR signals, making them particularly suited to be studied by standard NMR methods. SH2 domains are modular proteins whose function is the recognition of sequences containing phosphotyrosines. In this chapter, we describe the application of NMR to assess the interaction between SH2 domains and phosphopeptides and determine the structure of the resulting complexes.
MeSH term(s)	Phosphopeptides ; src Homology Domains ; Magnetic Resonance Imaging ; Phosphotyrosine ; Magnetic Resonance Spectroscopy
Chemical Substances	Phosphopeptides ; Phosphotyrosine (21820-51-9)
Language	English
Publishing date	2023-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3393-9_1
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Article ; Online: Specificity and regulation of phosphotyrosine signaling through SH2 domains.

Marasco, Michelangelo / Carlomagno, Teresa

Journal of structural biology: X

2020 Volume 4, Page(s) 100026

Abstract: Phosphotyrosine (pY) signaling is instrumental to numerous cellular processes. pY recognition occurs through specialized protein modules, among which the Src-homology 2 (SH2) domain is the most common. SH2 domains are small protein modules with an ... ...

Abstract	Phosphotyrosine (pY) signaling is instrumental to numerous cellular processes. pY recognition occurs through specialized protein modules, among which the Src-homology 2 (SH2) domain is the most common. SH2 domains are small protein modules with an invariant fold, and are present in more than a hundred proteins with different function. Here we ask the question of how such a structurally conserved, small protein domain can recognize distinct phosphopeptides with the breath of binding affinity, specificity and kinetic parameters necessary for proper control of pY-dependent signaling and rapid cellular response. We review the current knowledge on structure, thermodynamics and kinetics of SH2-phosphopeptide complexes and conclude that selective phosphopeptide recognition is governed by both structure and dynamics of the SH2 domain, as well as by the kinetics of the binding events. Further studies on the thermodynamic and kinetic properties of SH2-phosphopeptide complexes, beyond their structure, are required to understand signaling regulation.
Language	English
Publishing date	2020-05-27
Publishing country	United States
Document type	Journal Article
ISSN	2590-1524
ISSN (online)	2590-1524
DOI	10.1016/j.yjsbx.2020.100026
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Article: Experiment-guided molecular simulations define a heterogeneous structural ensemble for the

Marasco, Michelangelo / Kirkpatrick, John / Carlomagno, Teresa / Hub, Jochen S / Anselmi, Massimiliano

Chemical science

2023 Volume 14, Issue 21, Page(s) 5743–5755

Abstract: SHP2 plays an important role in regulating cellular processes, and its pathogenic mutations cause developmental disorders and are linked to cancer. SHP2 is a multidomain protein, comprising two SH2 domains arranged in tandem, a catalytic PTP domain, and ... ...

Abstract	SHP2 plays an important role in regulating cellular processes, and its pathogenic mutations cause developmental disorders and are linked to cancer. SHP2 is a multidomain protein, comprising two SH2 domains arranged in tandem, a catalytic PTP domain, and a disordered C-terminal tail. SHP2 is activated upon binding two linked phosphopeptides to its SH2 domains, and the peptide orientation and spacing between binding sites are critical for enzymatic activation. For decades, the tandem SH2 has been extensively studied to identify the relative orientation of the two SH2 domains that most effectively binds effectors. So far, neither crystallography nor experiments in solution have provided conclusive results. Using experiment-guided molecular simulations, we determine the heterogeneous structural ensemble of the tandem SH2 in solution in agreement with experimental data from small-angle X-ray scattering and NMR residual dipolar couplings. In the solution ensemble, N-SH2 adopts different orientations and positions relative to C-SH2. We suggest that the intrinsic structural plasticity of the tandem SH2 allows SHP2 to respond to external stimuli and is essential for its functional activity.
Language	English
Publishing date	2023-05-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d3sc00746d
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Article ; Online: Specificity and regulation of phosphotyrosine signaling through SH2 domains.

Marasco, Michelangelo / Carlomagno, Teresa

4 ; 100026 ; Journal of structural biology: X ; United States

2020

Abstract	Phosphotyrosine (pY) signaling is instrumental to numerous cellular processes. pY recognition occurs through specialized protein modules, among which the Src-homology 2 (SH2) domain is the most common. SH2 domains are small protein modules with an invariant fold, and are present in more than a hundred proteins with different function. Here we ask the question of how such a structurally conserved, small protein domain can recognize distinct phosphopeptides with the breath of binding affinity, specificity and kinetic parameters necessary for proper control of pY-dependent signaling and rapid cellular response. We review the current knowledge on structure, thermodynamics and kinetics of SH2-phosphopeptide complexes and conclude that selective phosphopeptide recognition is governed by both structure and dynamics of the SH2 domain, as well as by the kinetics of the binding events. Further studies on the thermodynamic and kinetic properties of SH2-phosphopeptide complexes, beyond their structure, are required to understand signaling regulation.
Keywords	Binding specificity ; Phosphotyrosine ; SH2 domain ; pY signalling
Subject code	572
Language	English
Publishing date	2020-05-27
Publisher	Elsevier
Publishing country	de
Document type	Article ; Online
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Article ; Online: 1

Marasco, Michelangelo / Kirkpatrick, John P / Carlomagno, Teresa

Biomolecular NMR assignments

2020 Volume 14, Issue 2, Page(s) 179–188

Abstract: Inhibition of immune checkpoint receptor Programmed Death-1 (PD-1) via monoclonal antibodies is an established anticancer immunotherapeutic approach. This treatment has been largely successful; however, its high cost demands equally effective, more ... ...

Abstract	Inhibition of immune checkpoint receptor Programmed Death-1 (PD-1) via monoclonal antibodies is an established anticancer immunotherapeutic approach. This treatment has been largely successful; however, its high cost demands equally effective, more affordable alternatives. To date, the development of drugs targeting downstream players in the PD-1-dependent signaling pathway has been hampered by our poor understanding of the molecular details of the intermolecular interactions involved in the pathway. Activation of PD-1 leads to phosphorylation of two signaling motifs located in its cytoplasmic domain, the immune tyrosine inhibitory motif (ITIM) and immune tyrosine switch motif (ITSM), which recruit and activate protein tyrosine phosphatase SHP2. This interaction is mediated by the two Src homology 2 (SH2) domains of SHP2, termed N-SH2 and C-SH2, which recognize phosphotyrosines pY223 and pY248 of ITIM and ITSM, respectively. SHP2 then propagates the inhibitory signal, ultimately leading to suppression of T cell functionality. In order to facilitate mechanistic structural studies of this signaling pathway, we report the resonance assignments of the complexes formed by the signaling motifs of PD-1 and the SH2 domains of SHP2.
MeSH term(s)	Amino Acid Motifs ; Carbon-13 Magnetic Resonance Spectroscopy ; Humans ; Nitrogen Isotopes ; Nuclear Magnetic Resonance, Biomolecular ; Programmed Cell Death 1 Receptor/chemistry ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/analysis ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/chemistry ; Proton Magnetic Resonance Spectroscopy ; Tyrosine/immunology ; src Homology Domains
Chemical Substances	Nitrogen Isotopes ; Nitrogen-15 ; Programmed Cell Death 1 Receptor ; Tyrosine (42HK56048U) ; PTPN11 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48)
Language	English
Publishing date	2020-04-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2388861-1
ISSN	1874-270X ; 1874-2718
ISSN (online)	1874-270X
ISSN	1874-2718
DOI	10.1007/s12104-020-09941-y
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Article: Phosphotyrosine couples peptide binding and SHP2 activation via a dynamic allosteric network.

Marasco, Michelangelo / Kirkpatrick, John / Nanna, Vittoria / Sikorska, Justyna / Carlomagno, Teresa

Computational and structural biotechnology journal

2021 Volume 19, Page(s) 2398–2415

Abstract: SHP2 is a ubiquitous protein tyrosine phosphatase, whose activity is regulated by phosphotyrosine (pY)-containing peptides generated in response to extracellular stimuli. Its crystal structure reveals a closed, auto-inhibited conformation in which the N- ... ...

Abstract	SHP2 is a ubiquitous protein tyrosine phosphatase, whose activity is regulated by phosphotyrosine (pY)-containing peptides generated in response to extracellular stimuli. Its crystal structure reveals a closed, auto-inhibited conformation in which the N-terminal Src homology 2 (N-SH2) domain occludes the catalytic site of the phosphatase (PTP) domain. High-affinity mono-phosphorylated peptides promote catalytic activity by binding to N-SH2 and disrupting the interaction with the PTP. The mechanism behind this process is not entirely clear, especially because N-SH2 is incapable of accommodating complete peptide binding when SHP2 is in the auto-inhibited state. Here, we show that pY performs an essential role in this process; in addition to its contribution to overall peptide-binding energy, pY-recognition leads to enhanced dynamics of the N-SH2 EF and BG loops via an allosteric communication network, which destabilizes the N-SH2-PTP interaction surface and simultaneously generates a fully accessible binding pocket for the C-terminal half of the phosphopeptide. Subsequently, full binding of the phosphopeptide is associated with the stabilization of activated SHP2. We demonstrate that this allosteric network exists only in N-SH2, which is directly involved in the regulation of SHP2 activity, while the C-terminal SH2 domain (C-SH2) functions primarily to recruit high-affinity bidentate phosphopeptides.
Language	English
Publishing date	2021-04-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2021.04.040
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Article ; Online: 1H, 13C, 15N chemical shift assignments of SHP2 SH2 domains in complex with PD-1 immune-tyrosine motifs.

Marasco, Michelangelo / Kirkpatrick, John P / Carlomagno, Teresa

Biomolecular NMR assignments ; Netherlands

2020

Abstract	Inhibition of immune checkpoint receptor Programmed Death-1 (PD-1) via monoclonal antibodies is an established anticancer immunotherapeutic approach. This treatment has been largely successful; however, its high cost demands equally effective, more affordable alternatives. To date, the development of drugs targeting downstream players in the PD-1-dependent signaling pathway has been hampered by our poor understanding of the molecular details of the intermolecular interactions involved in the pathway. Activation of PD-1 leads to phosphorylation of two signaling motifs located in its cytoplasmic domain, the immune tyrosine inhibitory motif (ITIM) and immune tyrosine switch motif (ITSM), which recruit and activate protein tyrosine phosphatase SHP2. This interaction is mediated by the two Src homology 2 (SH2) domains of SHP2, termed N-SH2 and C-SH2, which recognize phosphotyrosines pY223 and pY248 of ITIM and ITSM, respectively. SHP2 then propagates the inhibitory signal, ultimately leading to suppression of T cell functionality. In order to facilitate mechanistic structural studies of this signaling pathway, we report the resonance assignments of the complexes formed by the signaling motifs of PD-1 and the SH2 domains of SHP2.
Keywords	Immunotherapy ; PD-1 ; SH2 domains ; SHP2
Subject code	572
Language	English
Publishing date	2020-04-01
Publisher	Springer
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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