Kocher
Olivier Kocher, M.D., Ph.D.
Associate Professor of Pathology
Beth Israel Deaconess Medical Center
Harvard Medical School

330 Brookline Avenue, RN-270C
Boston, MA 02215
Office: 617-667-3598
Fax: 617-667-3591
Email:
okocher@bidmc.harvard.edu

Education/Training/Appointments:

1981, MD, Univ. of Geneva Medical School, Geneva, Switzerland; 1987, PhD, Univ. of Geneva, Faculty of Sciences (Biology), Geneva, Switzerland; 1987-1989, Post-doctoral fellow (Pathology) (Laboratory of Dr.J.A. Madri, Department of Pathology, Yale University, New Haven, Connecticut; 1989-1992, Residency (Pathology), Beth Israel Hospital, Boston, MA; 1992-present: Staff pathologist and researcher in the Department of Pathology at BIDMC.


Research Interests: Atherosclerosis, Cholesterol Metabolism & PDZK1

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Basic Research - Adaptor proteins play an important role in signal transduction.  Often the interaction between signaling proteins is mediated by small amino acid sequences binding to specific proteins domains, such as src homology, pTyr-binding (PTB) or PDZ domains. These interactions are responsible for determining location, function and activity of receptors and transporter proteins.  We isolated a novel protein that we named PDZK1. PDZK1 contains four PDZ protein-interactions domains and interacts with the carboxy-terminal portion of a number of membrane associated proteins including the high density lipoprotein (HDL) scavenger receptor SR-BI and several ion channels, one of them involved in multidrug resistance.  Therefore, PDZK1 is likely to play an important role in biological processes as diverse as lipid metabolism and cardiovascular disease, ion channel organization and multidrug resistance.

We generated a PDZK1 knockout mouse which is characterized by increased plasma cholesterol levels and markedly reduced expression of SR-BI in the liver, resulting in impaired “reverse cholesterol transport”. PDZK1 joins ARH (the product of the defective gene in autosomal recessive hypercholesterolemia) in what is likely to be a growing family of cytoplasmic adaptor proteins that control the tissue specific activity of cell surface receptors.

More recently, we have determined, using a transgenic mouse model in which truncated forms of PDZK1 were overexpressed in the liver of PDZK1 KO mice, that all four PDZ domains of PDZK1 are necessary for normal SR-BI expression, localization and function. We have determined that SR-BI is able to interact with PDZ3 within PDZK1, in addition to the known interaction with PDZ1. In addition, we have solved the crystal structures of the first and third domains of PDZK1 and its interaction with SR-BI. We have also determined that PDZK1 is atheroprotective, suggesting that PDZK1 may be an attractive target for therapies in cardiovascular diseases.


New and Noteworthy Publications:

Fenske SA, Yesilaltay A, Pal R, Daniels K, Rigotti A, Krieger M and Kocher O.
Overexpression of the PDZ1 domain of PDZK1 blocks the activity of hepatic scavenger receptor, class B, type I (SR-BI) by altering its abundance and cellular localization. J Biol Chem. 2008, 283:22097-22104.

Fenske SA, Yesilaltay A, Pal R, Daniels K, Barker C, Quiñones V, Rigotti A., Krieger M. and Kocher O. Normal hepatic cell-surface localization of the high-density lipoprotein receptor, SR-BI, depends on all four PDZ domains of PDZK1. J Biol Chem. 2009, 284:5797-5806.


Yesilaltay A, Daniels K, Pal R, Krieger M and Kocher O. Loss of PDZK1 causes coronary artery occlusion and myocardial infarction in Paigen diet-fed apolipoprotein E deficient mice. PloS ONE, 2009, 4 (12): e8103.

Kocher O, Birrane G, Tsukamoto K, Fenske S, Yesilaltay A, Pal R, Daniels K, Ladias JAA and Krieger M. In vitro and in vivo Analysis of the binding of the C-terminus of the HDL Receptor SR-BI to the PDZ1 domain of its Adaptor Protein PDZK1. J Biol Chem, 2010, 285:34999-35010.

Kocher O, Birrane G, Yesilaltay A, Shechter S, Pal R, Daniels K and Krieger M. Identification of the PDZ3 domain of the adaptor protein PDZK1 as a second, physiologically functional, binding site for the C-terminus of the HDL Receptor SR-BI. J Biol Chem, 2011,286:25171-25186.