Role of the Discoidin Domain receptor proteins in atherosclerosis: Interaction with lipids and collagen

Bibliographic Details
Main Author:	Nauerth, Michelle Jon
Language:	English
Published:	The Ohio State University / OhioLINK 2011
Subjects:	Biochemistry Discoidin Domain protein engineering
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=osu1316545109

id	ndltd-OhioLink-oai-etd.ohiolink.edu-osu1316545109
record_format	oai_dc
spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-osu13165451092021-08-03T06:04:03Z Role of the Discoidin Domain receptor proteins in atherosclerosis: Interaction with lipids and collagen Nauerth, Michelle Jon Biochemistry Discoidin Domain protein engineering <p>Discoidin domain receptors (DDR1 and DDR2) are unique tyrosine kinase receptors (RTKs) in that they bind to and become phosphorylated by collagens, particularly collagen type I; the most abundant protein in the extracellular matrix (ECM). It is currently not known if collagen is the only ligand for these proteins, since some members of the discoidin family also bind phospholipids via their discoidin domain. In either case, the mechanisms for binding any ligand by these two proteins are not completely understood. It is generally known that receptors from the RTK family bind a ligand and induce down-stream phosphorylation of the intracellular tyrosine kinase, thus controlling several cellular processes. The goal of this study is to demonstrate a possibility for alternative ligands, other than collagen, for the discoidin domain receptor proteins, and elucidate how a mechanism of binding may occur.</p><p>The data presented here qualitatively addresses the possibility that phospholipids may be a ligand for the DDRs. Several proteins in the blood coagulation pathway bind phospholipids via their discoidin-like domains. In addition, the three-dimensional crystal structures of these proteins have been resolved. Utilizing their amino acid sequence, as well as their three-dimensional structure as a template, a series of experiments was designed to elucidate a possible DDRs:phospholipid interaction. There is a strong indication, as my results demonstrate that DDRs bind to phospholipids. Three-dimensional molecular models of the DDRs were proposed and used to understand how these proteins might bind to a plasma membrane, which is comprised of phospholipids. The finished structure of the DDRs mimics those proteins in the blood coagulation pathway which bind phospholipids and support my hypothesis that DDRs may favor phospholipids as a ligand.</p><p> Based on the results of the molecular modeling study, the extracellular domain (ECD), which is the proposed ligand binding region of the DDRs, was employed in a series of experiments involving platelet aggregation. It is known that the preferred ligand for the DDRs is fibrillar collagen. The data presented in this study is novel, and shows that DDRs inhibit platelets from aggregating via an indirect interaction with collagen. These results may elucidate a possible role for the DDRs in arteriole plaque formation and rupture. </p><p> The last aim of this research involves the role of DDR1 in the remodeling of the extracellular matrix (ECM). The ECM contains three morphological forms of collagen; monomeric (M), semi-polymeric (SP), and fibrillar (F). As cells secrete M collagen, it forms a polymeric intermediate SP form, and eventually composes the fibrillar F form. The results of the study indicate the preferred ligand for DDR1 is the intermediate SP form of collagen type I in addition to the known F form. These results provide a better understanding of morphological collagen usage-initially during collagen processing in the ECM in response to vascular damage, and their interactions with DDRs.</p> 2011-10-21 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1316545109 http://rave.ohiolink.edu/etdc/view?acc_num=osu1316545109 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.
collection	NDLTD
language	English
sources	NDLTD
topic	Biochemistry Discoidin Domain protein engineering
spellingShingle	Biochemistry Discoidin Domain protein engineering Nauerth, Michelle Jon Role of the Discoidin Domain receptor proteins in atherosclerosis: Interaction with lipids and collagen
author	Nauerth, Michelle Jon
author_facet	Nauerth, Michelle Jon
author_sort	Nauerth, Michelle Jon
title	Role of the Discoidin Domain receptor proteins in atherosclerosis: Interaction with lipids and collagen
title_short	Role of the Discoidin Domain receptor proteins in atherosclerosis: Interaction with lipids and collagen
title_full	Role of the Discoidin Domain receptor proteins in atherosclerosis: Interaction with lipids and collagen
title_fullStr	Role of the Discoidin Domain receptor proteins in atherosclerosis: Interaction with lipids and collagen
title_full_unstemmed	Role of the Discoidin Domain receptor proteins in atherosclerosis: Interaction with lipids and collagen
title_sort	role of the discoidin domain receptor proteins in atherosclerosis: interaction with lipids and collagen
publisher	The Ohio State University / OhioLINK
publishDate	2011
url	http://rave.ohiolink.edu/etdc/view?acc_num=osu1316545109
work_keys_str_mv	AT nauerthmichellejon roleofthediscoidindomainreceptorproteinsinatherosclerosisinteractionwithlipidsandcollagen
_version_	1719430289250320384

Role of the Discoidin Domain receptor proteins in atherosclerosis: Interaction with lipids and collagen

Similar Items