MOLECULAR IDENTITY OF MATURE LYSOSOMAL ACID SPHINGOMYELINASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Acid sphingomyelinase (aSMase) catalyzes the hydrolysis of sphingomyelin (SM) to form the bioactive lipid ceramide (Cer). Notably, aSMase exists in two forms - a zinc (Zn)-independent lysosomal aSMase (L-SMase) and a Zn-dependent secreted aSMase (S-SMase) that arise from alternative trafficking of a single protein precursor. Despite extensive investigation into the maturation and trafficking of aSMase, the exact identity of mature L-SMase has remained unclear. We are interested in determining the molecular identity of mature L-SMase, specifically C-terminal proteolytic processing. Carboxy-terminal processing would represent a novel mechanism of post-translational regulation of aSMase, which has implications for the regulation of L-SMase activity and function, and may provide new insight into the molecular basis of Niemann-Pick disease.