Tissue specific regulation of the high density lipoprotein (HDL) receptor, scavenger receptor Class B, Type I (SR-BI) by the scaffold protein PDZK1

PDZK1 is a four PDZ-domain containing cytoplasmic adaptor protein that binds the Cterminus of the high-density lipoprotein (HDL) receptor SR-BI. Abolishing PDZK1 expression in PDZK1 knockout (KO) mice leads to a post-transcriptional, tissue-specific decrease in SR-BI protein level and an increase in total plasma cholesterol carried in abnormally-large HDL particles. A greater than 95% decrease in SR-BI expression levels is observed in the livers of PDZK1 KO mice. The mechanism behind this tissue-specific regulation of SR-BI expression is unclear. PDZK1 comprises multiple structural features that, aside from the first PDZ domain, which binds SR-BI, are not known to interact with SR-BI. It seems probable that these structures (three PDZ domains, at least one phosphorylation site on the C- terminal tail, and a putative PDZ-binding motif at its C-terminus) might interact with other cellular components to influence hepatic SR-BI expression. This thesis explores the role of PDZK1's structural features in the PDZK1-dependent regulation of hepatic SR-BI through the hepatic expression of PDZK1 and various truncation and point mutants of PDZK1 in wild-type (WT) and PDZK1 KO mice. These studies demonstrated that overexpression of the first PDZ domain of PDZK1 can affect hepatic SR-BI abundance and localization in both WT and PDZK1 KO mice, but was not sufficient to restore normal SR-BI function in PDZK1 KO mice. Overexpression of the first three domains of PDZK1 in PDZK1 KO mice was able to partially restore cell-surface localization and function of hepatic SR-BI, but was not able to fully restore SR-BI abundance, localization and abundance.

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Biology

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2008

Author dc:creator

• Fenske, Sara Anne

Advisor dc:contributor.advisor

• Monty Krieger.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/45805

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/45805