Figure 2. Salivary-statherin & MEPE consensus ASARM motif: mineralization-inhibition and ancestral genes on chromosome 4. MEPE, DMP-1, and the SIBLINGs are related to an ancestral mineralization-gene (salivary statherin) that is also thought to function in the transport of calcium and phosphate in salivary glands. Statherin maps to chromosome 4 in the SIBLING/MEPE region and also contains an ASARM motif. (A) A clustal alignment of the COOH terminal region of human-DMP-1, human-MEPE, mouse-MEPE, and rat-MEPE with human-statherin (62-residue protein). In MEPE and DMP-1, the ASARM peptide occupies the most distal COOH-region of the molecule and is highlighted with a boxed cartouche labeled ‘MEPE ASARM peptide’. The boxed cartouche labeled as ‘statherin-ASARM peptide’ contains the sequence shown to play a biological role in inhibiting spontaneous precipitation of supersaturated salivary calcium and phosphate and maintaining the mineralization dynamics of tooth enamel (Schlesinger and Hay, 1977; Bennick et al., 1981; Raj et al., 1992; Long et al., 1998). Statherin is also thought to function in the transport of calcium and phosphate in salivary glands (Raj et al., 1992). In both MEPE and statherin, cathepsin-B and/or general protease cleavage results in the release of MEPE and statherin protease-resistant ASARM peptides. Both MEPE and statherin ASARM peptides are phosphorylated, protease-resistant, acidic and highly charged molecules with low pI’s. They also share biological properties. For example, a feature of the MEPE ASARM region is the repeat (D) SSES/E sequence. This short sequence has been shown to be a key inhibitor of hydroxyapatite crystal formation and mineralization in salivary statherin (Raj et al., 1992; Long et al., 1998). (B) Schematic presentation of the remarkable clustering of MEPE, DMP-1, statherin, and other SIBLING genes on chromosome 4.