8.A.81 The S100 Calcium-binding protein (S100) Family 

S100 proteins and annexins are groups of Ca2+-binding proteins, each of which comprises more than 10 members in humans. S100 proteins are small, dimeric, EF-hand-type Ca2+-binding proteins that exert both intracellular and extracellular functions. Within the cells, S100 proteins regulate phosphorylation in response to changes in the intracellular Ca2+ concentration. S100 proteins are associated with many diseases (Miwa et al. 2008). Annexins are non-EF-hand-type Ca2+-binding proteins that exhibit Ca2+-dependent binding to phospholipids and membranes in various tissues. They bring different membranes into proximity and assist them to fuse, playing a role in membrane trafficking and organization. Several S100 proteins and annexins interact with each other and form complexes that exhibit biological activities. These complexes regulate the organization of membranes and vesicles and thereby participate in the appropriate disposition of membrane-associated proteins, including ion channels and/or receptors (Miwa et al. 2008).

Transient receptor potential melastatin-1 channel (TRPM1) mediates calcium influx into some cells in the body. Similar to other members of the TRP channel family, the intracellular N- and C-terminal domains of play roles in modulating TRPM1 receptor function. Among the most commonly occurring modulators of TRP channels are the cytoplasmically expressed calcium binding proteins calmodulin and S100 calcium-binding protein A1 (S100A1). Jirku et al. 2016 showed that the N-terminal region of TRPM1,  L242-E344, is a S100A1 binding domain. Formation of the TRPM1/S100A1 complex is calcium-dependent. Complex formation is facilitated through interactions with clusters of positively charged (K271A, R273A, R274A) and hydrophobic (L263A, V270A, L276A) residues in TRPM1. A molecular model for the regulation of TRPM1 by S100A1 was presented (Jirku et al. 2016). 

Human papillomaviruses (HPVs) cause benign and malignant tumors of the mucosal and cutaneous epithelium. HPV16 exposure to human keratinocytes initiates epidermal growth factor receptor (EGFR)-dependent Src protein kinase activation that results in phosphorylation and extracellular translocation of annexin A2 (AnxA2) (see TC# 9.A.48.1.1). HPV16 interacts with AnxA2 in association with S100A10 as a heterotetramer at the cell surface in a Ca2+-dependent manner, and the interaction appears to involve heparan-sulfonated proteoglycans. This interaction promotes virus uptake into host cells. An antibody to AnxA2 prevents HPV16 internalization, whereas an antibody to S100A10 blocks infection at a late endosomal/lysosomal site. Thus, AnxA2 and S100A10 have separate roles during HPV16 binding, entry, and trafficking (Dziduszko and Ozbun 2013).



Chen, W. and M. Kudryashev. (2020). Structure of RyR1 in native membranes. EMBO Rep 21: e49891.

Dziduszko, A. and M.A. Ozbun. (2013). Annexin A2 and S100A10 regulate human papillomavirus type 16 entry and intracellular trafficking in human keratinocytes. J. Virol. 87: 7502-7515.

Jirku, M., Z. Lansky, L. Bednarova, M. Sulc, L. Monincova, P. Majer, L. Vyklicky, J. Vondrasek, J. Teisinger, and K. Bousova. (2016). The characterization of a novel S100A1 binding site in the N-terminus of TRPM1. Int J Biochem. Cell Biol. [Epub: Ahead of Print]

Miwa, N., T. Uebi, and S. Kawamura. (2008). S100-annexin complexes--biology of conditional association. FEBS J. 275: 4945-4955.

Rescher, U. and V. Gerke. (2008). S100A10/p11: family, friends and functions. Pflugers Arch 455: 575-582.

Sturchler, E., J.A. Cox, I. Durussel, M. Weibel, and C.W. Heizmann. (2006). S100A16, a novel calcium-binding protein of the EF-hand superfamily. J. Biol. Chem. 281: 38905-38917.


TC#NameOrganismal TypeExample

The S100-A1 protein of 94 aas and 1 C-terminal TMS.  Regulates TRPM1 activity (Jirku et al. 2016) and the ryanodine receptor (Chen and Kudryashev 2020). It is capable of increasing the open probability of RyR1 and may compete with calmodulin (CaM, TC# 8.A.82) for the same binding site on the receptor (Chen and Kudryashev 2020).

S100-A1 of Homo sapiens


S100-A10 protein of 97 aas and 1 C-terminal TMS.  Interacts with annexin A2 to regulate intracellular trafficking and virus entry (Dziduszko and Ozbun 2013).  It also functions as a linker, tethering certain transmembrane proteins to annexin A2, thereby assisting trafficing to the plasma membrane and anchorage at certain membrane sites (Rescher and Gerke 2008).

S100-A10 of Homo sapiens


S100-A16 of 103 aas and 1 C-terminal TMS.  Binds one calcium ion per monomer (Sturchler et al. 2006).


S100-A16 of Homo sapiens


The S100-B protein of 92 aas. Weakly binds calcium but binds zinc very tightly-distinct binding sites with different affinities exist for both ions on each monomer. Physiological concentrations of potassium ion antagonize the binding of both divalent cations, especially affecting high-affinity calcium-binding sites. May mediate calcium-dependent regulation on many physiological processes by interacting with other proteins, such as TPR-containing proteins, and modulating their activity.

S100-B of Homo sapiens