Abstract
Osteopontin (OPN) is important for tissue remodeling, cellular immune responses, and calcium homeostasis in milk and urine. In pathophysiology, the biomolecule contributes to the progression of multiple cancers. Phylogenetic analysis of 202 osteopontin protein sequences identifies a core block of integrin-binding sites in the center of the protein, which is well conserved. Remarkably, the length of this block varies among species, resulting in differing distances between motifs within. The amino acid sequence SSEE is a candidate phosphorylation site. Two copies of it reside in the far N-terminus and are variably affected by alternative splicing in humans. Between those motifs, birds and reptiles have a histidine-rich domain, which is absent from other species. Just downstream from the thrombin cleavage site, the common motif (Q/I)(Y/S/V)(P/H/Y)D(A/V)(T/S)EED(L/E)(-/S)T has been hitherto unrecognized. While well preserved, it is yet without assigned function. The far C-terminus, although very different between Reptilia/Aves on the one hand and Mammals on the other, is highly conserved within each group of species, suggesting important functional roles that remain to be mapped. Taxonomic variations in the osteopontin sequence include a lack of about 20 amino acids in the downstream portion, a small unique sequence stretch C-terminally, a lack of six amino acids just upstream of the RGD motifs, and variable length insertions far C-terminally.
Highlights
Osteopontin (OPN) is a protein with fundamental functions in biology
In the splice variant osteopontin-c, two transglutamination sites are lost, and both SSEE motifs are brought into close proximity in the sequence DSGSSEEKQ-NAVSSEETND around the splice junction
Histidine-rich malaria proteins may activate the inflammasome, resulting in decreased integrity of tight junctions and increased endothelial permeability [18], functions that hypothetically could have been acquired by avian osteopontin. (It is notable that, across all species analyzed, a distinct, rather histidine-rich region is located just upstream of the C-terminus, reflected in the primate sequence HEFHSHEFHSH.)
Summary
Osteopontin (OPN) is a protein with fundamental functions in biology. While the name of the molecule is a misnomer—it does not critically contribute to the structural integrity of connective tissue or the skeleton [1,2]—it is broadly important for tissue remodeling [1,3], acts as a Th1 inducer cytokine [4], and regulates calcium homeostasis in milk and urine [5,6]. The far N-terminus contains splice sites that can generate the short forms osteopontin-b and -c [14] While their patho-biological effects in cancer have recently been elucidated, their direct binding partners remain unknown. In the splice variant osteopontin-c, two transglutamination sites are lost, and both SSEE motifs are brought into close proximity in the sequence DSGSSEEKQ-NAVSSEETND around the splice junction (marked by a hyphen). Even though only the splice variant osteopontin-c is abundant in the nucleus [13], there is no apparent nuclear localization sequence, K(K/R)X(K/R), in closeness to the splice junction, and the loss of exon 4 does not generate a candidate bipartite nuclear localization motif. Homologies resulting from a BLASTP search and a motif search in ELM identify similarities of the perijunctional sequence to nuclear proteins (Table 1B), corroborating that osteopontin-c may have a function in the cell nucleus. Histidine-rich malaria proteins may activate the inflammasome, resulting in decreased integrity of tight junctions and increased endothelial permeability [18], functions that hypothetically could have been acquired by avian osteopontin. (It is notable that, across all species analyzed, a distinct, rather histidine-rich region is located just upstream of the C-terminus, reflected in the primate sequence HEFHSHEFHSH.)
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