Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


kent1216671104.pdf (2.26 MB)

ETD Abstract Container

Abstract Header

Characterization of Binding of PTEN and its Disease Related Mutants to Phospholipid Model Membranes

Redfern, Roberta E.
http://rave.ohiolink.edu/etdc/view?acc_num=kent1216671104

Abstract Details

2008, PHD, Kent State University, College of Arts and Sciences / Department of Chemistry.
PTEN, phosphatase and tensin homologue deleted on chromosome 10, is a tumor suppressor that is commonly lost or mutated in many different diseases, including cancer, Bannayan Zonana syndrome, heart disease and cancer. The mechanism of the effects of the loss or mutation of PTEN is not known, other than the effects on the regulation of downstream effector molecules. While many other research groups have studied the effects of PTEN loss or mutation on tumor formation in mouse models, no group has undergone the daunting task of characterizing the protein biophysically, in order to determine how these mutations affect the actual action of the protein. In this study, we have shown that PTEN binds specifically to PI(4,5)P2 over all other phosphoinositides, including its substrate, PI(3,4,5)P3. This binding event is also associated with a conformational change, which is believed to activate the protein and increase its rate of turnover of PI(3,4,5)P3. Additionally, we shown in these studies that the binding specificity of PTEN is dependent on the presence and identity of the N-terminus, which contains a PI(4,5)P2 binding domain. Removal or mutation of the protein's N-terminus abrogates the binding and thus activity of the protein. One particular amino acid which is often mutated in many forms of cancer, the lysine in position 13, has been shown to be extremely important in the interaction of PTEN with PI(4,5)P2 containing membranes. We show that even while maintaining overall charge of the N-terminus and even overall identity, mutation of the lysine in this position results in a loss of binding specificity. We have also studied the binding of an autism related mutation of PTEN, which results in an increased binding to phosphatidylserine, which may play a role in the ability of the protein to turnover its substrate in vivo. We have also studied the effects of cholesterol on the binding of proteins to phosphoinositide containing membranes, which has proven to have different effects on the binding of different proteins. Finally, we show that phosphoinositides form domains in model membranes in the absence of proteins and the presence of cholesterol appears to enhance these formations.
Arne Gericke (Advisor)
Biochemistry
PTEN; phosphoinositides; PI3K pathway; cholesterol

Recommended Citations

Citations

  • Redfern, R. E. (2008). Characterization of Binding of PTEN and its Disease Related Mutants to Phospholipid Model Membranes [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1216671104

    APA Style (7th edition)

  • Redfern, Roberta. Characterization of Binding of PTEN and its Disease Related Mutants to Phospholipid Model Membranes. 2008. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1216671104.

    MLA Style (8th edition)

  • Redfern, Roberta. "Characterization of Binding of PTEN and its Disease Related Mutants to Phospholipid Model Membranes." Doctoral dissertation, Kent State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=kent1216671104

    Chicago Manual of Style (17th edition)

kent1216671104
661
© 2008, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.