Towards Understanding the Cell Adhesion Mediated by Non-clustered Non-classical Protocadherins
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The Ohio State University / OhioLINK
2021
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=osu1605887233542288 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu16058872335422882021-09-16T05:10:20Z Towards Understanding the Cell Adhesion Mediated by Non-clustered Non-classical Protocadherins Gray, Michelle Elizabeth Biochemistry Biology Biophysics cadherins cell adhesion protocadherins cancer gut epithelia calcium-mediated adhesion morphogenesis intermicrovillar adhesion complex CDH17 PCDH24 CDHR5 cadherin 17 protocadherin 24 mucin-like protocadherin x-ray crystallography Cell adhesion is an incredibly important process for multicellular life and is essential for development and maintenance of tissues, immunological response, cancer suppression and mechanosensation. The cadherin superfamily of calcium-dependent cell-adhesion proteins is a large group of diverse glycoproteins which play roles in the processes listed above. The superfamily can be broken down in roughly three subfamilies: classical cadherins, clustered protocadherins, and non-clustered protocadherins. Of those subfamilies, the cadherins in the non-clustered protocadherins have the most diverse range of adhesive functions. To mediate adhesion, cadherins make use of their extracellular domain, which is composed of tandem extracellular cadherin (EC) repeats. Within the repeat sequence, conserved motifs are present encoding for residues which bind three calcium ions at the linker region between repeats, thus imparting rigidity to the extracellular domain. Calcium binding is essential for adhesive function to occur. Here, I focus on several unique non-clustered protocadherins which use their ectodomains to help support the development and tissue morphogenesis of various systems.My work on the 7D-cadherins has focused primarily on cadherin 17 (CDH17) and its homophilic adhesion relevant for the function of the intestinal epithelia. In addition, its sibling, cadherin 16 (CDH16), is expected to mediate similar adhesion in the kidney epithelia. Structures of CDH17 EC1-2 reveal that the 7D-cadherins are unique and distinct from their relatives, the classical cadherins, in that they lack the tryptophan necessary for the conserved strand-swap interaction observed in classical cadherins. Bead aggregation assays using the full ectodomain of CDH17 as well as N- and C-terminal truncation series reveal that CDH17 relies on its EC7, but not its EC1 repeat, to carry out trans adhesion. A mutation in EC1 interferes with aggregation of the full-length ectodomain, indicating the entire ectodomain of CDH17 might be important for adhesion.My work on the intermicrovillar link cadherins, protocadherin 24 (PCDH24) and mucin-like protocadherin (CDHR5), revealed that there are several species-dependent differences on a structural and functional level. The structures of the N-terminal tips of human and mouse PCDH24 are different despite the proteins performing the same function in both human and mouse. The structure of human CDHR5 EC1-2 is canonical. In homophilic bead aggregation assays, human but not mouse PCDH24 can form homophilic contacts while with CDHR5, mouse but not human version of this protein can form homophilic interactions. Both species are capable of forming heterophilic interactions, though the repeats necessary for the interaction differ between human and mouse. Overall, my work has shed light on the structures and potential adhesive interfaces of a few non-clustered, non-classical cadherins. Additionally, my work has revealed that evolutionary differences occur between homologous proteins, even in closely related species. 2021-09-09 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1605887233542288 http://rave.ohiolink.edu/etdc/view?acc_num=osu1605887233542288 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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English |
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NDLTD |
| topic |
Biochemistry Biology Biophysics cadherins cell adhesion protocadherins cancer gut epithelia calcium-mediated adhesion morphogenesis intermicrovillar adhesion complex CDH17 PCDH24 CDHR5 cadherin 17 protocadherin 24 mucin-like protocadherin x-ray crystallography |
| spellingShingle |
Biochemistry Biology Biophysics cadherins cell adhesion protocadherins cancer gut epithelia calcium-mediated adhesion morphogenesis intermicrovillar adhesion complex CDH17 PCDH24 CDHR5 cadherin 17 protocadherin 24 mucin-like protocadherin x-ray crystallography Gray, Michelle Elizabeth Towards Understanding the Cell Adhesion Mediated by Non-clustered Non-classical Protocadherins |
| author |
Gray, Michelle Elizabeth |
| author_facet |
Gray, Michelle Elizabeth |
| author_sort |
Gray, Michelle Elizabeth |
| title |
Towards Understanding the Cell Adhesion Mediated by Non-clustered Non-classical Protocadherins |
| title_short |
Towards Understanding the Cell Adhesion Mediated by Non-clustered Non-classical Protocadherins |
| title_full |
Towards Understanding the Cell Adhesion Mediated by Non-clustered Non-classical Protocadherins |
| title_fullStr |
Towards Understanding the Cell Adhesion Mediated by Non-clustered Non-classical Protocadherins |
| title_full_unstemmed |
Towards Understanding the Cell Adhesion Mediated by Non-clustered Non-classical Protocadherins |
| title_sort |
towards understanding the cell adhesion mediated by non-clustered non-classical protocadherins |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2021 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1605887233542288 |
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AT graymichelleelizabeth towardsunderstandingthecelladhesionmediatedbynonclusterednonclassicalprotocadherins |
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1719481258192404480 |