Nobel Laureate Lecture Series in Mahatma Gandhi University

(on Dec.6, 2010, 10.30 AM, School of Chemical Sciences auditorium)

Title: Structural studies on cholesterol transport  

Johann Deisenhofer, Regental Professor 

The University of Texas Southwestern Medical Center Dallas, USA

 

Abstract : Cholesterol is essential for mammals; it is produced internally or taken up with the diet and transported in the blood stream in the form of lipoproteins, with low density lipoprotein (LDL) being most abundant. LDL is bound at cell surfaces by receptors and internalized. Inside cells, LDL particles are released from the receptors, degraded in lysosomes, and cholesterol is transported by specific binding proteins to its destinations. I will describe four studies on structural aspects of cholesterol transport:
Electron microscopy of low density lipoprotein (LDL) with and without bound LDL receptor protein shows size, shape and internal structure of typical LDL particles (1). The crystal structure of the extracellular portion of human LDL receptor (2) at pH 5.3 illustrates the domain organization of the receptor, and suggests possible mechanisms for LDL release at low pH. The recently discovered protein PCSK9 binds to the LDL receptor and appears to regulate the degradation of the receptors. A crystal structure of the complex of PCSK9 with a fragment of the LDL receptor (3) defines the binding interface and could lead to the development of new cholesterol-lowering drugs. Mutations in the proteins NPC1 and NPC2 can cause Niemann-Pick disease by slowing down or preventing the transport of cholesterol out of lysosomes. The crystal structure of the N-terminal domain of NPC1 with and without bound cholesterol (4) sheds light on the intra-lysosomal cholesterol transport pathway. 

References :

(1) Ren, G., Rudenko, G., Ludtke, S.J., Deisenhofer, J., Chiu, W., Pownall, H.J. (2010). PNAS 107, 1059-1064. 
(2) Rudenko, G., Henry, L., Henderson, K., Ichtchenko, K., Brown, M.S., Goldstein, J.L., Deisenhofer, J. (2002), Science 298, 2353-2358. 
(3) Kwon, H.J., Lagace, T.A., McNutt, M.C., Horton, J.D., and Deisenhofer, J. (2008). PNAS 105, 1820-1825. (4) Kwon, H.J., Abi-Mosleh, L., Wang, M.L., Deisenhofer, J., Goldstein, J.L., Brown, M.S., and Infante, R.E. (2009). Cell 137, 1213-1224.

(Prof.Deisenhofer will be in Mahatma Gandhi University Campus during Dec.5-10, 2010 for interaction with students/faculties/other researchers)

Profile of Dr. Johann Deisenhofer

  Johann Deisenhofer is Regental Professor and Professor in Biochemistry, and holds the Virginia and Edward Linthicum Distinguished Chair in Biomolecular Science at the University of Texas Southwestern Medical Center at Dallas; he is also Investigator in the Howard Hughes Medical Institute. Deisenhofer is a Member of the National Academy of Sciences of the USA, the Academia Europaea, the German Academy of Natural Scientists Leopoldina, and the Texas Academy of Science, Engineering, and Medicine. 

Deisenhofer earned his doctorate from the Technical University of Munich for research work done at the Max Planck Institute for Biochemistry in Martinsried, West Germany, in 1974. He conducted research there until 1988, when he joined the scientific staff of the Howard Hughes Medical Institute and the faculty of the Department of Biochemistry at The University of Texas Southwestern Medical Center at Dallas.

  Together with Michel and Huber, Deisenhofer determined the three-dimensional structure of a protein complex found in certain photosynthetic bacteria. This membrane protein complex, called a photosynthetic reaction center, was known to play a crucial role in initiating a simple type of photosynthesis. Between 1982 and 1985, the three scientists used X-ray crystallography to determine the exact arrangement of the more than 10,000 atoms that make up the protein complex. Their research increased the general understanding of the mechanisms of photosynthesis and revealed similarities between the photosynthetic processes of plants and bacteria. The structure of the reaction center helped explain the detailed mechanism of the conversion of light energy into chemical energy in photosynthesis, a biological process upon which almost all life on our planet depends. For this work he shared the 1986 Biological Physics Prize of the American Physical Society, and the 1988 Otto-Bayer-Prize with Hartmut Michel, and the 1988 Nobel Prize in Chemistry with Hartmut Michel and Robert Huber.