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  1. Article ; Online: The PB1 and the ZZ domain of the autophagy receptor p62/SQSTM1 regulate the interaction of p62/SQSTM1 with the autophagosome protein LC3B.

    Alcober-Boquet, Lucia / Zang, Tabea / Pietsch, Larissa / Suess, Evelyn / Hartmann, Markus / Proschak, Ewgenij / Gross, Lissy Z F / Sacerdoti, Mariana / Zeuzem, Stefan / Rogov, Vladimir V / Leroux, Alejandro E / Piiper, Albrecht / Biondi, Ricardo M

    Protein science : a publication of the Protein Society

    2023  Volume 33, Issue 1, Page(s) e4840

    Abstract: Autophagy is a highly conserved cellular process that allows degradation of large macromolecules. p62/SQSTM1 is a key adaptor protein that interacts both with material to be degraded and with LC3 at the autophagosome, enabling degradation of cargos such ... ...

    Abstract Autophagy is a highly conserved cellular process that allows degradation of large macromolecules. p62/SQSTM1 is a key adaptor protein that interacts both with material to be degraded and with LC3 at the autophagosome, enabling degradation of cargos such as protein aggregates, lipid droplets and damaged organelles by selective autophagy. Dysregulation of autophagy contributes to the pathogenesis of many diseases. In this study, we investigated if the interaction of p62/SQSTM1 with LC3B could be regulated. We purified full-length p62/SQSTM1 and established an in vitro assay that measures the interaction with LC3B. We used the assay to determine the role of the different domains of p62/SQSTM1 in the interaction with LC3B. We identified a mechanism of regulation of p62/SQSTM1 where the ZZ and the PB1 domains regulate the exposure of the LIR-sequence to enable or inhibit the interaction with LC3B. A mutation to mimic the phosphorylation of a site on the ZZ domain leads to increased interaction with LC3B. Also, a small compound that binds to the ZZ domain enhances interaction with LC3B. Dysregulation of these mechanisms in p62/SQSTM1 could have implications for diseases where autophagy is affected. In conclusion, our study highlights the regulated nature of p62/SQSTM1 and its ability to modulate the interaction with LC3B through a LIR-sequence Accessibility Mechanism (LAM). Furthermore, our findings suggest the potential for pharmacological modulation of the exposure of LIR, paving the way for future therapeutic strategies.
    MeSH term(s) Autophagosomes/metabolism ; Sequestosome-1 Protein/genetics ; Sequestosome-1 Protein/metabolism ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Autophagy/genetics
    Chemical Substances Sequestosome-1 Protein ; Microtubule-Associated Proteins ; Adaptor Proteins, Signal Transducing
    Language English
    Publishing date 2023-11-20
    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.4840
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  2. Article: Allosteric Regulation of Protein Kinases Downstream of PI3-Kinase Signalling.

    Leroux, Alejandro E / Gross, Lissy Z F / Sacerdoti, Mariana / Biondi, Ricardo M

    Advances in experimental medicine and biology

    2019  Volume 1163, Page(s) 279–311

    Abstract: Allostery is a basic principle that enables proteins to process and transmit cellular information. Protein kinases evolved allosteric mechanisms to transduce cellular signals to downstream signalling components or effector molecules. Protein kinases ... ...

    Abstract Allostery is a basic principle that enables proteins to process and transmit cellular information. Protein kinases evolved allosteric mechanisms to transduce cellular signals to downstream signalling components or effector molecules. Protein kinases catalyse the transfer of the terminal phosphate from ATP to protein substrates upon specific stimuli. Protein kinases are targets for the development of small molecule inhibitors for the treatment of human diseases. Drug development has focussed on ATP-binding site, while there is increase interest in the development of drugs targeting alternative sites, i.e. allosteric sites. Here, we review the mechanism of regulation of protein kinases, which often involve the allosteric modulation of the ATP-binding site, enhancing or inhibiting activity. We exemplify the molecular mechanism of allostery in protein kinases downstream of PI3-kinase signalling with a focus on phosphoinositide-dependent protein kinase 1 (PDK1), a model kinase where small compounds can allosterically modulate the conformation of the kinase bidirectionally.
    MeSH term(s) Allosteric Regulation ; Allosteric Site ; Drug Development ; Humans ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Binding/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases/metabolism ; Signal Transduction/drug effects
    Chemical Substances Protein Kinase Inhibitors ; Protein Kinases (EC 2.7.-) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
    Language English
    Publishing date 2019-10-31
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2214-8019 ; 0065-2598
    ISSN (online) 2214-8019
    ISSN 0065-2598
    DOI 10.1007/978-981-13-8719-7_12
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  3. Article ; Online: ACE2, the Receptor that Enables Infection by SARS-CoV-2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators.

    Gross, Lissy Z F / Sacerdoti, Mariana / Piiper, Albrecht / Zeuzem, Stefan / Leroux, Alejandro E / Biondi, Ricardo M

    ChemMedChem

    2020  Volume 15, Issue 18, Page(s) 1682–1690

    Abstract: Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID-19). Thus, ACE2 is a potential target for drugs that disrupt the ... ...

    Abstract Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID-19). Thus, ACE2 is a potential target for drugs that disrupt the interaction of human cells with SARS-CoV-2 to abolish infection. There is also interest in drugs that inhibit or activate ACE2, that is, for cardiovascular disorders or colitis. Compounds binding at alternative sites could allosterically affect the interaction with the spike protein. Herein, we review biochemical, chemical biology, and structural information on ACE2, including the recent cryoEM structures of full-length ACE2. We conclude that ACE2 is very dynamic and that allosteric drugs could be developed to target ACE2. At the time of the 2020 pandemic, we suggest that available ACE2 inhibitors or activators in advanced development should be tested for their ability to allosterically displace the interaction between ACE2 and the spike protein.
    MeSH term(s) Allosteric Regulation ; Angiotensin-Converting Enzyme 2 ; Angiotensin-Converting Enzyme Inhibitors/chemistry ; Angiotensin-Converting Enzyme Inhibitors/metabolism ; Betacoronavirus/chemistry ; Catalytic Domain ; Humans ; Peptidyl-Dipeptidase A/chemistry ; Peptidyl-Dipeptidase A/metabolism ; Protein Binding ; Protein Domains ; Receptors, Virus/antagonists & inhibitors ; Receptors, Virus/chemistry ; Receptors, Virus/metabolism ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism
    Chemical Substances Angiotensin-Converting Enzyme Inhibitors ; Receptors, Virus ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Keywords covid19
    Language English
    Publishing date 2020-08-11
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2218496-X
    ISSN 1860-7187 ; 1860-7179
    ISSN (online) 1860-7187
    ISSN 1860-7179
    DOI 10.1002/cmdc.202000368
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  4. Article ; Online: ACE2, the Receptor that Enables Infection by SARS‐CoV‐2

    Gross, Lissy Z. F. / Sacerdoti, Mariana / Piiper, Albrecht / Zeuzem, Stefan / Leroux, Alejandro E. / Biondi, Ricardo M.

    ChemMedChem

    Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators

    2020  Volume 15, Issue 18, Page(s) 1682–1690

    Keywords General Pharmacology, Toxicology and Pharmaceutics ; Organic Chemistry ; Molecular Medicine ; covid19
    Language English
    Publisher Wiley
    Publishing country us
    Document type Article ; Online
    ZDB-ID 2218496-X
    ISSN 1860-7187 ; 1860-7179
    ISSN (online) 1860-7187
    ISSN 1860-7179
    DOI 10.1002/cmdc.202000368
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  5. Article ; Online: Synergistic Allostery in Multiligand-Protein Interactions.

    Ghode, Abhijeet / Gross, Lissy Z F / Tee, Wei-Ven / Guarnera, Enrico / Berezovsky, Igor N / Biondi, Ricardo M / Anand, Ganesh S

    Biophysical journal

    2020  Volume 119, Issue 9, Page(s) 1833–1848

    Abstract: Amide hydrogen-deuterium exchange mass spectrometry is powerful for describing combinatorial coupling effects of a cooperative ligand pair binding at noncontiguous sites: adenosine at the ATP-pocket and a docking peptide (PIFtide) at the PIF-pocket, on a ...

    Abstract Amide hydrogen-deuterium exchange mass spectrometry is powerful for describing combinatorial coupling effects of a cooperative ligand pair binding at noncontiguous sites: adenosine at the ATP-pocket and a docking peptide (PIFtide) at the PIF-pocket, on a model protein kinase PDK1. Binding of two ligands to PDK1 reveal multiple hotspots of synergistic allostery with cumulative effects greater than the sum of individual effects mediated by each ligand. We quantified this synergism and ranked these hotspots using a difference in deuteration-based approach, which showed that the strongest synergistic effects were observed at three of the critical catalytic loci of kinases: the αB-αC helices, and HRD-motif loop, and DFG-motif. Additionally, we observed weaker synergistic effects at a distal GHI-subdomain locus. Synergistic changes in deuterium exchange observed at a distal site but not at the intermediate sites of the large lobe of the kinase reveals allosteric propagation in proteins to operate through two modes. Direct electrostatic interactions between polar and charged amino acids that mediate targeted relay of allosteric signals, and diffused relay of allosteric signals through soft matter-like hydrophobic core amino acids. Furthermore, we provide evidence that the conserved β-3 strand lysine of protein kinases (Lys111 of PDK1) functions as an integrator node to coordinate allosteric coupling of the two ligand-binding sites. It maintains indirect interactions with the ATP-pocket and mediates a critical salt bridge with a glutamate (Glu130) of αC helix, which is conserved across all kinases. In summary, allosteric propagation in cooperative, dual-liganded enzyme targets is bidirectional and synergistic and offers a strategy for combinatorial drug development.
    MeSH term(s) Allosteric Regulation ; Allosteric Site ; Binding Sites ; Ligands ; Peptides ; Protein Kinases/metabolism
    Chemical Substances Ligands ; Peptides ; Protein Kinases (EC 2.7.-)
    Language English
    Publishing date 2020-09-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/j.bpj.2020.09.019
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  6. Article: ACE2, the Receptor that Enables Infection by SARS-CoV-2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators

    Gross, Lissy Z F / Sacerdoti, Mariana / Piiper, Albrecht / Zeuzem, Stefan / Leroux, Alejandro E / Biondi, Ricardo M

    ChemMedChem

    Abstract: Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID-19). Thus, ACE2 is a potential target for drugs that disrupt the ... ...

    Abstract Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID-19). Thus, ACE2 is a potential target for drugs that disrupt the interaction of human cells with SARS-CoV-2 to abolish infection. There is also interest in drugs that inhibit or activate ACE2, that is, for cardiovascular disorders or colitis. Compounds binding at alternative sites could allosterically affect the interaction with the spike protein. Herein, we review biochemical, chemical biology, and structural information on ACE2, including the recent cryoEM structures of full-length ACE2. We conclude that ACE2 is very dynamic and that allosteric drugs could be developed to target ACE2. At the time of the 2020 pandemic, we suggest that available ACE2 inhibitors or activators in advanced development should be tested for their ability to allosterically displace the interaction between ACE2 and the spike protein.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #641524
    Database COVID19

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  7. Article ; Online: Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein.

    Sacerdoti, Mariana / Gross, Lissy Z F / Riley, Andrew M / Zehnder, Karin / Ghode, Abhijeet / Klinke, Sebastián / Anand, Ganesh Srinivasan / Paris, Kristina / Winkel, Angelika / Herbrand, Amanda K / Godage, H Yasmin / Cozier, Gyles E / Süß, Evelyn / Schulze, Jörg O / Pastor-Flores, Daniel / Bollini, Mariela / Cappellari, María Victoria / Svergun, Dmitri / Gräwert, Melissa A /
    Aramendia, Pedro F / Leroux, Alejandro E / Potter, Barry V L / Camacho, Carlos J / Biondi, Ricardo M

    Science signaling

    2023  Volume 16, Issue 789, Page(s) eadd3184

    Abstract: The activation of at least 23 different mammalian kinases requires the phosphorylation of their hydrophobic motifs by the kinase PDK1. A linker connects the phosphoinositide-binding PH domain to the catalytic domain, which contains a docking site for ... ...

    Abstract The activation of at least 23 different mammalian kinases requires the phosphorylation of their hydrophobic motifs by the kinase PDK1. A linker connects the phosphoinositide-binding PH domain to the catalytic domain, which contains a docking site for substrates called the PIF pocket. Here, we used a chemical biology approach to show that PDK1 existed in equilibrium between at least three distinct conformations with differing substrate specificities. The inositol polyphosphate derivative HYG8 bound to the PH domain and disrupted PDK1 dimerization by stabilizing a monomeric conformation in which the PH domain associated with the catalytic domain and the PIF pocket was accessible. In the absence of lipids, HYG8 potently inhibited the phosphorylation of Akt (also termed PKB) but did not affect the intrinsic activity of PDK1 or the phosphorylation of SGK, which requires docking to the PIF pocket. In contrast, the small-molecule valsartan bound to the PIF pocket and stabilized a second distinct monomeric conformation. Our study reveals dynamic conformations of full-length PDK1 in which the location of the linker and the PH domain relative to the catalytic domain determines the selective phosphorylation of PDK1 substrates. The study further suggests new approaches for the design of drugs to selectively modulate signaling downstream of PDK1.
    MeSH term(s) Animals ; Substrate Specificity ; Phosphorylation ; Catalytic Domain ; Dimerization ; Polyphosphates ; Mammals
    Chemical Substances Polyphosphates
    Language English
    Publishing date 2023-06-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.add3184
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