Séminaires MSC
"Matière et Systèmes Complexes"

Lundi 17 mai 2010 à 11h30
Bâtiment Condorcet, 4ème étage, salle 454 A.

Galya Staneva
(Institute of Biophysics, Bulgarian Academy of Sciences)

How model membranes can contribute to the understanding of molecular basis of defective microdomains assembly in Smith-Lemli-Opitz syndrome?


Smith-Lemli-Opitz syndrome (SLOS) is a metabolic and developmental disorder that affects many parts of the body. This illness is characterized by distinctive facial features, small head size (microcephaly), mental retardation or learning disabilities, and behavioral problems. Malformations of the heart, lungs, kidney, gastrointestinal tract and genitalia, hypocholesteromia and paleness are also common. Most affected individuals have fused second and third toes (syndactyly), and some have extra fingers or toes (polydactyly). Mutations in the DHCR7 gene cause Smith-Lemli-Opitz syndrome. The DHCR7 gene makes an enzyme called 7-dehydrocholesterol reductase. Mutations in the DHCR7 gene reduce or eliminate the activity of 7-dehydrocholesterol reductase, preventing cells from producing enough cholesterol. Cholesterol is an essential nutrient that is necessary for normal embryonic development. Cholesterol is also a structural component of cell membranes and the protective substance covering nerve cells (myelin). The combination of low cholesterol levels and an accumulation of 7-dehydrocholesterol disrupts the growth and development of many body systems. At present, it is not known how this disturbance in cholesterol production leads to the specific features of Smith-Lemli-Opitz syndrome. There are currently two hypotheses to explain the cell defects of SLOS embryonic cells. The first is that 7-dehydrocholesterol is not able to substitute for cholesterol as a component of the cell membranes and secondly, the cleavage of the morphogenic protein, Sonic Hedgehog (SHH) is defective in the presence of 7-dehydrocholesterol. Both cholesterol and 7-dehydrocholesterol are known to augment cleavage of the N-terminal signalling peptide from SHH. Because the reaction to remove the signal peptide takes place in membrane “raft” domains which are enriched in cholesterol the two explanations for SLO syndrome may be reconciled. It is possible that replacement of cholesterol by 7-dehydrocholesterol produces membrane domains that are unable to provide the necessary structural environment for post-translational modification of SHH. How model membranes can contribute to the understanding of molecular basis of defective microdomains assembly with participation of 7-dehydrocholesterol will be presented during the seminar? The research is approached by three independent methods: fluorescence microscopy, X-ray diffraction and electron spin resonance spectroscopy.