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A second unresolved question relates to potential roles of S2P and S1P in proteolytic processing of other proteins in addition to SREBPs. As noted above, hydrophobic proteins that resemble S2P, including the putative zinc-binding site, are found as far back as Archaea. This suggests that S2P may play more general housekeeping roles in addition to processing SREBPs.

S1P also may play a more general role in proteolytic cleavage. S1P is the first vertebrate subtilisin whose sequence more closely resembles the bacterial members of this family as compared with the mammalian members. This finding is consistent with the observation that S1P cleaves SREBP after a hydrophobic leucine residue rather than after a basic residue. S1P also appears to act in a pre-Golgi compartment, which differs from the prohormone convertases, which generally act in the Golgi or in post-Golgi compartments (53, 54). The requirement for SCAP suggests that the activity of S1P may be restricted to SREBPs because no other proteins are known to require SCAP for cleavage. Moreover, cells that lack S1P grow normally as long as they are supplied with the end-products of the SREBP pathway (48). On the other hand, the finding that S1P (or SKI-1) can cleave pro-brain-derived neurotrophic factor when overexpressed in intact cells or in vitro raises the possibility that the protease may have broader actions. This argument is rendered less persuasive by the observation that the site in pro-brain-derived neurotrophic factor that is cleaved by S1P does not correspond to the major site of physiologic pro-brain-derived neurotrophic factor processing in vivo (58, 59).

Clearly, the intense study of S1P and S2P is only beginning. Given the rich scientific experience with other proteases, all of the unresolved questions about these two reactions will likely be answered in the near future. These answers should markedly advance our knowledge of cholesterol homeostasis.

This work was supported by research grants from the National Institutes of Health (HL20948) and the Perot Family Foundation.

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