Proteolytic signals in the primary structure of annexins.

Annexins are a superfamily of calcium-dependent membrane-associated proteins which interact with phospholipids. The primary structure of Annexins I, III, VII, VIII and XI contain a region enriched in proline, glutamate, serine and threonine (PEST sequences) towards the N-terminal end while annexins II, V and VI possess PEST regions somewhat distal to the N-terminus. These PEST sequences are believed to be the signals for rapid intracellular degradation. Annexin I is known to be cleaved by calpain near its PEST region suggesting that its PEST region might be a possible calpain recognition site. Western blot analysis of annexins V and XI in rat lung homogenates suggest that these proteins are resistant to proteolysis by calpain. Annexin V was found to be stable to intrinsic lung proteases in the presence of either Ca2+ or EGTA while annexin XI was found to be partially degraded by intrinsic lung proteases in the presence of EGTA. Eight of the 10 known mammalian annexins also contain a pentapeptide sequence that is biochemically related to the KFERQ motif which is a known signal that targets protein for lysosomal proteolysis. Our data suggest that the annexins may be regulated by limited proteolysis, most likely at their N-terminal end, while most, if not all, of them might be degraded by the lysosomal pathway.