S100A13 belonging to S100 protein family was discovered in 1996 in the laboratory of Claus W. Heizmann (Wicki et al. 1996). The S100A13 gene is localized on human chromosome 1q21 in the cluster of genes coding for other S100 proteins (Ridinger et al. 1998). High levels of S100A13 expression were reported for skeletal muscle, heart, kidney, ovary, small intestine, and pancreas (Ridinger et al. 2000).
S100A13 and Nonclassical Protein Export (FGF1, IL1α, Prothymosin)
Similar to other members of S100 family, S100A13 is secreted despite the absence in its structure of a signal peptide required for translocation into the lumen of the endoplasmic reticulum (ER) (Landriscina et al. 2001). NIH3T3 cells transfected with S100A13 spontaneously release it through an unconventional ER-Golgi independent pathway (Landriscina et al. 2001). S100A13 has been detected in a brain-derived heparin-binding multiprotein complex that also contains three other secreted signal peptide-less proteins: Annexin 2, 40 kDa alternatively translated form of synaptotagmin 1 (p40 Syt1), and fibroblast growth factor 1 (FGF1) (Prudovsky et al. 2003). Unlike S100A13, FGF1 is released from fibroblasts only at stress conditions, such as heat shock, hypoxia, and removal of growth factors (Prudovsky et al. 2003). S100A13 is a critically important component of FGF1 release pathway. When coexpressed with FGF1, S100A13 export becomes stress-dependent, and both proteins are released as a complex (Landriscina et al. 2001). The distinguishing characteristic of S100A13 is a C-terminal domain rich in basic amino acids (Landriscina et al. 2001). Deletion of this domain results in a dominant-negative S100A13 mutant that suppresses FGF1 export (Landriscina et al. 2001). Release of S100A13 in complex with FGF1 was also demonstrated for astrocytes (Matsunaga and Ueda 2006). In addition to FGF1, S100A13 was shown to be critical for the stress-induced release of the signal peptide-less cytokine IL1α (Mandinova et al. 2003). S100A13 is also released from ischemic neurons in a complex with the cell survival promoting signal peptide-less protein prothymosin (Halder et al. 2012).
Interactions with Ions, Proteins, and Lipids
The most notable difference between S100A13 and the other members of the S100 family is the differential binding affinity of two EF-hand motifs to Ca2+. The shorter canonical Ca2+-binding loop has a higher binding affinity (Kd ∼ 105-10-6 M) for metal ions than that of the longer “pseudo” Ca2+-binding loop (Kd ∼ 10-3 M). In marked contrast to that, in other S100 members the Ca2+-binding affinity of both the EF-hand motifs is similar. The presence of the low-affinity “pseudo” Ca2+-binding loop is very consistent with the intracellular location of S100A13 related to its transmembrane release. Indeed, the local concentration of Ca2+ in the vicinity of the inner surface of the cell membrane, wherein S100A13 is prevalent (Prudovsky et al. 2003), is significantly higher (McLaughlin 1989). Binding of Ca2+ causes subtle but significant change in the relative orientations of helices in S100A13. Ca2+ binding changes the angle between helices α3 and α4 by ∼ 40° (Arnesano et al. 2005). The change in relative orientations of helices α3 and α3′, upon binding to Ca2+, causes a drastic change in the topology of helices α4 and α4′. As a consequence, helix α3 is nearly perpendicularly positioned with respect to helix α4.
As it was discussed above, S100A13 plays a critical role in the nonclassical secretion of FGF1. It forms a Cu2+-mediated multiprotein release complex consisting of FGF1 and p40 Syt1. S100A13 binds Cu2+ and Ca2+ with almost similar binding affinities (Rajalingam et al. 2005). The binding of Cu2+ and Ca2+ is not mutually exclusive. Two of each Ca2+ and Cu2+ ions bind per subunit of S100A13, and these two metal ions have opposite effects on the thermodynamic stability of S100A13. The former stabilizes the protein and the latter causes destabilizing effects.
In agreement with its transmembrane export, S100A13 shows preferential binding to unilamellar vesicles of phosphatidyl serine (pS), a lipid, selectively enriched in the inner leaflet of the cell membrane. Binding of S100A13 to pS results in significant conformational change and increases the solvent exposed nonpolar solvent interface (Rajalingam et al. 2005).
S100A13 in Cell Stress, Cancer, and Thrombosis
The transcription of S100A13 is upregulated by various types of stress. For example, the level of S100A13 mRNA increases after gamma irradiation of oral keratinocytes (Lambros et al. 2011). One can suggest that the increase of S100A13 expression may contribute to the nonclassical export of partner signal peptide-less proteins, such as FGF1, IL1α, and prothymosine. Interestingly, stimulation of S100A13 expression occurs also in rat frontal cortex at such a form of stress as electroconvulsive seizure treatment (Huang and Chen 2008).
Increased levels of S100A13 expression were reported for melanomas especially in melanoma-associated capillaries (Massi et al. 2010) and thyroid carcinomas where it is exported to the cyst fluid (Dinets et al. 2015).
S100A13 binds the platelet receptor CLEC-2 involved in thrombosis (Inoue et al. 2015). Immobilized S100A13 increases thrombus formation in vitro on collagen-coated surfaces (Inoue et al. 2015). It has been detected in the luminal area of atherosclerotic lesions (Inoue et al. 2015).
S100A13 is a stress-induced small signal peptide-less protein expressed in many types of cells and tissues In spite of absence of a signal peptide in its primary structure, S100A13 is spontaneously released from the cells through a Golgi-independent mechanism. It forms copper-dependent complexes with FGF1 and IL1α and participates in stress-induced nonclassical export of these proteins. Extracellular S100A13 binds the receptor for advanced glycation end products (RAGE). S100A13 could be involved in the pathogenesis of certain types of tumors and in thrombosis.