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).