Biochemistry Seminar: Olivier Kocher, Harvard Medical School
Wed, Mar 12
12:00 PM — 1:00 PM
MarshakCity College of New York160 Convent Avenue
"Regulation of the HDL receptor SR-BI expression by the multi PDZ domain adaptor protein PDZK1"ABSTRACT
Scaffolding, anchoring, and adaptor proteins residing at the cell membrane/cytoplasm interface have been recognized as playing a critical role in regulating various biological processes, including signal transduction, adhesion, membrane trafficking, and cellular transport. A large number of these proteins contain specific amino-acid sequences such as src-homology, phosphotyrosine-binding (PTB), and PDZ domains that are used to link integral membrane and non-membranous proteins into functional complexes.
A few years ago, we discovered a novel protein that we named PDZK1. PDZK1 is a 63 kD protein containing four PDZ protein interaction domains. Using a large number of molecular, biophysical and biochemical techniques, as well as mouse models that we produced (knockout and transgenic mice), we have determined that PDZK1 interacts with and controls the expression of a number of cell surface molecules such as ion channels (one of them involved in multidrug resistance) and cell surface receptors.
Most importantly, we defined PDZK1 as the tissue specific regulator and adaptor protein for the high density lipoprotein (HDL) receptor called scavenger receptor class B type I (SR-BI).
We generated a PDZK1 knockout mouse and made the important observation that PDZK1 controls - in a tissue specific, post-transcriptional fashion - the expression of the HDL receptor SR-BI and HDL metabolism. Therefore, PDZK1 joins a growing family of cytoplasmic adaptor proteins that control the tissue-specific activity of cell surface receptors. Among the cell surface receptors playing major roles in regulating plasma cholesterol levels are members of the low-density lipoprotein (LDL) receptor superfamily (LDL receptor, LRP, etc.), which are regulated by intracellular adaptors, including ARH (autosomal recessive hypercholesterolemia), and the high-density lipoprotein (HDL) receptor, scavenger receptor class B type I (SR-BI), one of several cell surface proteins that are regulated by the intracellular adaptor PDZK1.
These findings define PDZK1 as a molecule that plays a critical role in biological processes as diverse as lipid metabolism and cardiovascular disease, ion channel organization and cancer biology.
With the support of NIH funding, we are further characterizing PDZK1 using a combination of in vitro (molecular, biophysical techniques and structural biology) and in vivo modalities (knockout, transgenic and knockin mouse models) with the goal of developing drugs which promote reverse cholesterol transport and could decrease the incidence of cardiovascular disease.