The Role of Non-Motif Selectivity Determinants in PDZ Domain-Binding Interactions
Research Mentor(s)
Amacher, Jeanine
Description
An important class of protein-protein interactions in the cell involve recognition of short linear motifs (SLiMs) or peptides which often have a relatively weak affinity and transient. Dysregulation of SLiM-binding domains and target interactions are implicated in a number of human diseases. Due to the recognition of only a couple of amino acid positions by SLiM-binding domains, interaction networks greatly overlap and specific targeting is hard to achieve. The PDZ domain was used as a model system in order to define the role of non-motif selectivity determinants in SLiM- or peptide-mediated interactions. They recognize the extreme C-terminus of target proteins and binding motifs are based on only two residues. Dissecting the binding networks of over 250 PDZ domains using only motif preferences is impossible. Likewise, two sequences can bind drastically different numbers of PDZ domains. For example, the C-terminal sequence of the human papillomavirus E6 oncoprotein (HPV16 E6) interacts with over a dozen PDZ domain-containing proteins, while the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR) interacts with less than five, yet both contain identical motif residues. We reveal that single-residue substitution of peptides and structural biology allow us to determine non-motif selectivity determinants for multiple PDZ domains that target the HPV16 E6 oncoprotein. In addition, we present the first known crystal structure of a PDZ domain from choanoflagellates, our closest non-metazoan ancestor, and describe non-motif selectivity determinants in these unique organisms. We show that non-motif specificity is critical in order to characterize SLiM interactions networks in the cell.
Document Type
Event
Start Date
15-5-2019 9:00 AM
End Date
15-5-2019 5:00 PM
Location
Carver Gym (Bellingham, Wash.)
Department
Chemistry
Genre/Form
student projects, posters
Subjects – Topical (LCSH)
Carrier proteins; Domain structure
Type
Image
Rights
Copying of this document in whole or in part is allowable only for scholarly purposes. It is understood, however, that any copying or publication of this document for commercial purposes, or for financial gain, shall not be allowed without the author’s written permission.
Language
English
Format
application/pdf
The Role of Non-Motif Selectivity Determinants in PDZ Domain-Binding Interactions
Carver Gym (Bellingham, Wash.)
An important class of protein-protein interactions in the cell involve recognition of short linear motifs (SLiMs) or peptides which often have a relatively weak affinity and transient. Dysregulation of SLiM-binding domains and target interactions are implicated in a number of human diseases. Due to the recognition of only a couple of amino acid positions by SLiM-binding domains, interaction networks greatly overlap and specific targeting is hard to achieve. The PDZ domain was used as a model system in order to define the role of non-motif selectivity determinants in SLiM- or peptide-mediated interactions. They recognize the extreme C-terminus of target proteins and binding motifs are based on only two residues. Dissecting the binding networks of over 250 PDZ domains using only motif preferences is impossible. Likewise, two sequences can bind drastically different numbers of PDZ domains. For example, the C-terminal sequence of the human papillomavirus E6 oncoprotein (HPV16 E6) interacts with over a dozen PDZ domain-containing proteins, while the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR) interacts with less than five, yet both contain identical motif residues. We reveal that single-residue substitution of peptides and structural biology allow us to determine non-motif selectivity determinants for multiple PDZ domains that target the HPV16 E6 oncoprotein. In addition, we present the first known crystal structure of a PDZ domain from choanoflagellates, our closest non-metazoan ancestor, and describe non-motif selectivity determinants in these unique organisms. We show that non-motif specificity is critical in order to characterize SLiM interactions networks in the cell.