Acidic lipids enhance cathepsin D cleavage of the myelin basic protein.
Some acidic lipids including sulfatide and phosphatidylinositol were found to increase greatly the rate of cathepsin D cleavage of the myelin basic protein. Since a similar effect was seen when the substrate was changed to cytochrome C, but not when the enzyme was changed to pepsin, these acidic lipids seem to be acting on cathepsin D rather than on myelin basic protein itself. Even so, chemical modification studies suggest that this phenomenon is only seen when the myelin basic protein is in its native conformation. Succinylation of MBP increases its rate of cleavage by cathepsin D by at least tenfold and, in addition, with this modified and presumably denatured MBP as substrate, activation of cathepsin D is no longer seen with acidic lipids. These findings suggest that the native conformation of MBP is both an important determinant of its rate of cleavage by cathepsin D and is also essential for observing activation of this reaction by acidic lipids. The acidic lipids seem to alter the "extended active site" of cathepsin D in such a way as to enable this enzyme better to utilize the native myelin basic protein as a substrate. Cathepsin D has previously been implicated as the protease responsible for the release into cerebrospinal fluid in multiple sclerosis patients of an encephalitogenic fragment derived from myelin basic protein. It is possible that the elevated levels of cathepsin D and sulfatide that have previously been found associated with multiple sclerosis plaques in vivo act in concert to bring about the rapid cleavage and subsequent loss of the myelin basic protein from these localized regions in the myelin sheath.
Williams
K R
KR
Williams
N D
ND
Konigsberg
W
W
Yu
R K
RK
D000818:Animals; D001921:Brain / Q000201:enzymology; D002402:Cathepsin D / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D002417:Cattle; D004789:Enzyme Activation / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D004676:Myelin Basic Protein / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000494:pharmacology*; D013379:Substrate Specificity; D013433:Sulfoglycosphingolipids / Q000494:pharmacology*
D004676:Myelin Basic Protein; D010716:Phosphatidylinositols; D013433:Sulfoglycosphingolipids; D002402:Cathepsin D