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Cytoplasmic Domain of Human Myelin Protein Zero Likely Folded as ß-Structure in Compact Myelin

XiaoYang Luo ^*, Deepak Sharma ^*, Hideyo Inouye ^*, Daniel Lee ^*, Robin L. Avila ^*, Mario Salmona  and Daniel A. Kirschner ^*

^* Department of Biology, Boston College, Chestnut Hill, Massachusetts; and Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy

Correspondence: Address reprint requests to Daniel A. Kirschner, Tel.: 617-552-0211; E-mail: kirschnd{at}bc.edu.

Myelin protein zero (P0 or P0 glycoprotein), the major integral membrane protein in peripheral nervous system myelin, plays a key role in myelin membrane compaction and stability. While the structure of P0 extracellular domain was determined by crystallography, the paucity of any structural data on the highly positive-charged P0 cytoplasmic domain (P0-cyt) has greatly limited our understanding of the mechanism of P0 function. Here, using circular dichroism and intrinsic fluorescence spectroscopy, we attempted to elucidate the structure of human P0-cyt (hP0-cyt) in membrane mimetic environments composed of detergents or lipid vesicles. We found that the secondary structure of P0-cyt was polymorphic—at the lipid/protein ratio corresponding to that of mature peripheral myelin (50:1), hP0-cyt mainly adopted a ß-conformation, whereas when the proportion of lipid increased, the structure underwent a ß transition. By contrast, the secondary structure of the major isoform of myelin basic protein, another myelin protein with a very large positive charge, remained unchanged across a wide range of lipid/protein ratios. We propose that when hP0-cyt is bound at sufficient concentration to lamellar lipid bilayers such as myelin, it folds into a ß-conformation; before this threshold lipid/protein ratio is reached, the domain is -helical. We suggest that the cytoplasmic apposition (major dense line) in compact myelin may be stabilized via the hydrogen-bonding of ß-strands formed as a result of local P0-P0 aggregation.

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				X. Luo, H. Inouye, A. A. R. Gross, M. M. Hidalgo, D. Sharma, D. Lee, R. L. Avila, M. Salmona, and D. A. Kirschner Cytoplasmic Domain of Zebrafish Myelin Protein Zero: Adhesive Role Depends on {beta}-Conformation Biophys. J., November 15, 2007; 93(10): 3515 - 3528. [Abstract] [Full Text] [PDF]