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1. Revoredo, Leslie. Characterizing the (Glyco)peptide Substrate Specificities of the ppGalNAc T Family of Glycosyltransferases.

Degree: PhD, Chemistry, 2016, Case Western Reserve University

Many proteins of eukaryotic cells are known to be O-glycosylated. Glycoproteins with heavily O-glycosylated mucin domains provide important biological functions in a cell: i.e., protection from pathogens, cell-to-cell adhesion and intracellular protein trafficking. Mucin-type O-glycosylation occurs in the Golgi complex and begins with the transfer of GalNAc from UDP-GalNAc onto Ser/Thr residues of polypeptides. This step is catalyzed by a large family (20) called N-a-acetylgalactosaminyl transferases (ppGalNAc-T’s) and forms the GalNAc-a-O-Ser/Thr product. Subsequent elongation is performed by specific glycosyltransferases, producing a variety of glycans. Family members have been classified into peptide- and glycopeptide-preferring subfamilies, although both subfamilies possess variable activities against glycopeptide substrates. Structurally, 19 isoforms contain a C-terminal catalytic domain linked via a flexible linker to an N-terminal ricin-like lectin domain. The (glyco)peptide substrate specificities of the ppGalNAc-T transferases and the roles of the catalytic and lectin domains in glycopeptide glycosylation still remain largely unknown. Based on the systematic random peptide approach created by the Gerken Lab, I have determined the glycopeptide substrate specificities of several ppGalNAc-T isoforms. A series of (glyco)peptides were created in order to specifically probe the functions of the catalytic and lectin domains in terms of neighboring (1-5 residues) and remote prior glycosylation (6-17 residues) from an acceptor site, respectfully. Using several glycopeptide-preferring isoforms, glycosylation was observed from -4, -3, -1 and +1 relative to a neighboring GalNAc-O-Thr, which I attributed to specific GalNAc-O-Thr binding at the catalytic domain. The other series of glycopeptides contained a GalNAc-O-Thr near the C- or N- terminus of the substrate to address the directionality preferences of the lectin domain. Results with several peptide- and glycopeptide-preferring isoforms revealed preferences that varied among transferase isoform, where some preferred a C-terminally placed GalNAc-O-Thr, or a N-terminally placed GalNAc-O-Thr and others equally preferred the C-/N- terminally placed GalNAc-O-Thr. These directionality preferences are due to the GalNAc-O-Thr interactions at the lectin domain. Results of these studies revealed for the first time the site-specific glycopeptide glycosylation preferences by some ppGalNAc-T’s and has demonstrated that both domains of the ppGalNAc-T’s have specialized and unique functions that work in concert to control and order mucin-type O-glycosylation. Advisors/Committee Members: Gerken, Thomas (Advisor), Lee, Irene (Committee Chair).

Subjects/Keywords: Biochemistry; Chemistry; Mucin-type O-linked glycosylation; ppGalNAc T; lectin domain

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APA (6th Edition):

Revoredo, L. (2016). Characterizing the (Glyco)peptide Substrate Specificities of the ppGalNAc T Family of Glycosyltransferases. (Doctoral Dissertation). Case Western Reserve University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=case1464000374

Chicago Manual of Style (16th Edition):

Revoredo, Leslie. “Characterizing the (Glyco)peptide Substrate Specificities of the ppGalNAc T Family of Glycosyltransferases.” 2016. Doctoral Dissertation, Case Western Reserve University. Accessed April 01, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1464000374.

MLA Handbook (7th Edition):

Revoredo, Leslie. “Characterizing the (Glyco)peptide Substrate Specificities of the ppGalNAc T Family of Glycosyltransferases.” 2016. Web. 01 Apr 2020.

Vancouver:

Revoredo L. Characterizing the (Glyco)peptide Substrate Specificities of the ppGalNAc T Family of Glycosyltransferases. [Internet] [Doctoral dissertation]. Case Western Reserve University; 2016. [cited 2020 Apr 01]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1464000374.

Council of Science Editors:

Revoredo L. Characterizing the (Glyco)peptide Substrate Specificities of the ppGalNAc T Family of Glycosyltransferases. [Doctoral Dissertation]. Case Western Reserve University; 2016. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1464000374

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