Di Carluccio, Cristina (2022) NMR and computational studies of the molecular recognition of eukaryotic glycans by receptor proteins. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Resource language: English
Title: NMR and computational studies of the molecular recognition of eukaryotic glycans by receptor proteins
Di Carluccio, Cristinacristina.dicarluccio@unina.it
Date: 10 March 2022
Number of Pages: 258
Institution: Università degli Studi di Napoli Federico II
Department: Scienze Chimiche
Dottorato: Scienze chimiche
Ciclo di dottorato: 34
Coordinatore del Corso di dottorato:
Lombardi, Angelinaangelina.lombardi@unina.it
Molinaro, AntonioUNSPECIFIED
Date: 10 March 2022
Number of Pages: 258
Keywords: NMR spectroscopy, sialoglycans, molecular interactions
Settori scientifico-disciplinari del MIUR: Area 03 - Scienze chimiche > CHIM/06 - Chimica organica
Date Deposited: 21 Mar 2022 11:35
Last Modified: 28 Feb 2024 10:53
URI: http://www.fedoa.unina.it/id/eprint/14435

Collection description

All living cells are covered by a layer of glycans at the interface between the environment and the cell membrane, capable of mediating cellular behavior, including critical mechanisms in immunoregulation and pathological processes. The molecular recognition of glycoconjugates from several proteins triggers a plethora of biological functions, especially in the infection process, immune response, and inflammation. Within this frame, interactions between glycans and their binding partners at molecular level have been studied, using a multidisciplinary approach of advanced NMR techniques, including ligand- and protein-based approaches, in combination with biophysical and computational methodologies, such as docking and molecular dynamic simulations. Siglecs (Sialic acid-binding immunoglobulin-type lectins) exploit a major application in the immune system regulation, recognizing glycans containing sialic acid. Indeed, in their cytoplasmic region, Siglecs contain one or multiple tyrosine-based signaling motifs that trigger cellular signaling, inhibiting the immune cell activation. In this thesis, the molecular bindings of different inhibitory Siglecs, in particular Siglec-2 and -7, containing cytosolic immunoreceptor tyrosine-based inhibition motifs (ITIMs), have been investigated with several glycoconjugates. Although the inhibition of immune system plays a fundamental role in some aberrant events, such as the over-reaction of response against self-molecules that often leads to produce autoimmune diseases, it is worth knowing that many pathogens have evolved the ability to cover their surfaces of sialic acids, subverting the immune system and dampening the host immune recognition. Thus, Siglecs have been studied as attractive targets for the design of therapeutic agents, such as antibodies or glycomimetics, for the treatment of inflammatory, autoimmune, and infectious diseases. In the case of Siglec-2, or CD22, the binding mode with complex-type N-glycans has been assessed, showing the possibility to form CD22 homo-oligomers on the B-cell surface, favoring the cis interactions on the same cell. As for Siglec-7, mainly located on NK cells, novel structural insights have been provided on its binding to sialylated lipopolysaccharides on different strains of the oncogenic pathogen F. nucleatum, with the aim to develop therapies for the modulation of both Siglec-7 activity and host-pathogen binding. On the other hand, bacterial adhesins, also implicated in the biology of infection, as in the bacterial pathogenesis, have been studied in interaction with their cognate ligands. In particular, Siglec-like adhesins, similar to Siglecs in the V-set N-terminal domain of sialoglycan recognition, are serine-rich repeat glycoproteins involved in the pathogenesis of infective endocarditis. In this context, the binding site of Siglec-like adhesins expressed on different strains of Streptococci has been investigated in interaction with a variety of sialylated N- and O-glycans. Partially related systems have been also investigated during the PhD, involving the study of the interactions between monoclonal antibodies (mAb) against bacterial glycoconjugates (and mimetics). Therefore, the molecular details of different glycans recognized by mammalian and bacterial proteins, as well as monoclonal antibodies, that play roles in health and disease, or host-pathogen interactions have been unveiled to provide a tool for the design of glycomimetics for therapeutic targets of human diseases.


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