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Structural Investigation of the Complex of Filamin A Repeat 21 with Integrin αIIb and β3 Cytoplasmic Tails – A Potential “Transmission” to Regulate Cell Migration

Liu, Jianmin
http://rave.ohiolink.edu/etdc/view?acc_num=csu1263314406

Abstract Details

2009, Doctor of Philosophy in Clinical-Bioanalytical Chemistry, Cleveland State University, College of Science.
Cell functions in multi-cellular organisms are strongly depend on the dynamic cooperation between cell adhesion and cytoskeleton reorganization. Integrins, the major cell adhesion receptors, bind to extracellular matrix (ECM) and soluble ligands on the cell surface and link to the actin cytoskeleton inside the cell membrane. In this manner, integrins integrate cell adhesion and cytoskeleton reorganization by acting as a mechanical force transducer and a biochemical signaling hub (Zamir and Geiger 2001). Consequently, integrins are vital for development, immune responses, leukocyte traffic and hemostasis, and a variety of other cellular and physiological processes. Integrins are also are the focal point of many human diseases, including genetic, autoimmune, cardiovascular and others. In terms of the cell-ECM adhesion, integrins can exist in two major states, active, where it binds to appropriate extracellular ligands, and inactive, where it disassociates from extracellular ligands. The cellular pathways that modify the integrin extracellular ligand binding states have been called inside-out integrin signaling while the pathways that are mediated by the extracellular binding have been called outside-in integrin signaling. Although the directions of outside-in and inside-out signaling point to each other, they often happen reciprocally. Rather than just integrins alone accomplishing integrin signaling, numerous proteins are recruited around integrins and are limited to the clearly defined range of focal adhesion that are large molecular complexes containing >100 proteins which link integrins to cytoskeleton (Figure 1) (Zaidel-Bar et al. 2004). Proteins that directly interact with integrins are crucial for understanding integrin signaling. More importantly, proteins that link integrins to the cytoskeleton are responsible for both mechanical forces and biochemical signal transduction, as well as reorganizing the cytoskeleton. Moreover, the modification of integrin ligand binding states is dependent on the linkage to the cytoskeleton. Filamin is one of the main proteins that link integrins to the cytoskeleton and it has profound significance in integrin-mediated cell functions. Human filamin is a dimeric actin-binding protein, consisting of an actin-binding domain followed by 24 immunoglobulin repeats with the last repeat being the dimerization motif. Of the 24 immunoglobulin repeats of filamin, repeat 21(FLN21) has been characterized as a major integrin binding partner. The results in this dissertation provide a molecular level understanding of integrin-filamin interaction. A mechanism of how the integrin-filamin complex integrates cell adhesion mediation and cytoskeleton reorganization was proposed based on the determined structure and other biophysical and biochemical studies. Nuclear magnetic resonance (NMR) is a powerful method for studying protein structure and protein-protein interactions, provided by advances in the high resolution and accuracy of NMR. Since the structural nature of protein is the foundation of understanding all biological and physiologic processes, I believe the results presented here shape the integrin field.
Edward Plow, PhD (Advisor)
Jun Qin, PhD (Committee Member)
Yan Xu, PhD (Committee Member)
John Masnovi, PhD (Committee Member)
Aimin Zhou, PhD (Committee Member)
126 p.
Analytical Chemistry; Biochemistry; Biomedical Research; Biophysics; Chemistry
Structural biology; NMR; integrin; filamin; cell migration

Recommended Citations

Citations

  • Liu, J. (2009). Structural Investigation of the Complex of Filamin A Repeat 21 with Integrin αIIb and β3 Cytoplasmic Tails – A Potential “Transmission” to Regulate Cell Migration [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1263314406

    APA Style (7th edition)

  • Liu, Jianmin. Structural Investigation of the Complex of Filamin A Repeat 21 with Integrin αIIb and β3 Cytoplasmic Tails – A Potential “Transmission” to Regulate Cell Migration . 2009. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1263314406.

    MLA Style (8th edition)

  • Liu, Jianmin. "Structural Investigation of the Complex of Filamin A Repeat 21 with Integrin αIIb and β3 Cytoplasmic Tails – A Potential “Transmission” to Regulate Cell Migration ." Doctoral dissertation, Cleveland State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=csu1263314406

    Chicago Manual of Style (17th edition)

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© 2009, all rights reserved.
This open access ETD is published by Cleveland State University and OhioLINK.