Efficient trafficking of acidic proteins out of the endoplasmic reticulum involves a conserved amino terminal IleProVal (IPV)-like tripeptide motif.

[dentinogenesis imperfecta]

Most of the proposed extracellular biomineralization processes include the secretion of proteins that interact with mineral ions and /or mineral surfaces . Typically these proteins are acidic or have acidic domains that interact with multivalent cations in the extracellular environment . We propose that most acidic , Ca (2 +)-binding proteins challenge the cell 's mechanisms for trafficking through the endoplasmic reticulum (ER ) lumen due to lumenal mM calcium that cause them to form large aggregates . We have recently shown that >95 % of the DSPP mutations that cause non-syndromic genetic dentin diseases start their dominant negative affects by failing to rapidly exit the ER likely by forming complexes that can not be normally trafficked to the Golgi . The complexes of mutant DSPP then capture more (severe disease ) or less (mild disease ) of the DSPP translated from the normal allele . After searching genomic databases as well as the published literature , we found the IleProVal (IPV )-like motif at the predicted amino terminus of many acidic proteins made in the mineralizing as well as non-mineralizing tissues of many species including vertebrates , echinoderms , mollusks , and yeast . While we often focused on acidic proteins reported associated with mineralizing structures , proteins associated with hormones and their storage /secretion , digestion , blood functions , as well as milk and other secreted fluids started with variations of the motif . Our hypothesis is that the IPV-like motif interacts with a highly conserved cargo receptor in the ER that efficiently traffics the acidic proteins out of the organelle before they can form harmful aggregates in the Ca (2 +)-rich lumen .