S100–annexin complexes – structural insights

Abstract

Annexins and S100 proteins represent two large, but distinct, calcium‐binding protein families. Annexins are made up of a highly α‐helical core domain that binds calcium ions, allowing them to interact with phospholipid membranes. Furthermore, some annexins, such as annexins A1 and A2, contain an N‐terminal region that is expelled from the core domain on calcium binding. These events allow for the interaction of the annexin N‐terminus with target proteins, such as S100. In addition, when an S100 protein binds calcium ions, it undergoes a structural reorientation of its helices, exposing a hydrophobic patch capable of interacting with its targets, including the N‐terminal sequences of annexins. Structural studies of the complexes between members of these two families have revealed valuable details regarding the mechanisms of the interactions, including the binding surfaces and conformation of the annexin N‐terminus. However, other S100–annexin interactions, such as those between S100A11 and annexin A6, or between dicalcin and annexins A1, A2 and A5, appear to be more complicated, involving the annexin core region, perhaps in concert with the N‐terminus. The diversity of these interactions indicates that multiple forms of recognition exist between S100 proteins and annexins. S100–annexin interactions have been suggested to play a role in membrane fusion events by the bridging together of two annexin proteins, bound to phospholipid membranes, by an S100 protein. The structures and differential interactions of S100–annexin complexes may indicate that this process has several possible modes of protein–protein recognition.

S100 and annexin proteins identify cell membrane damage as the Achilles heel of metastatic cancer cells

“…46 These proteins undergo a change in conformation upon binding calcium, which exposes a hydrophobic domain that can interact with the NH2-terminal region of specific annexins. 44 This interaction facilitates close apposition of adjacent phospholipid membranes and promotes membrane fusion. 33 Additionally, several pair of S100-annexin complexes such as S100A10 and annexin A2 (S100A10-ANXA2) can bind cytoskeletal components and have been associated with intracellular vesicle fusion.…”

“…47 S100A10 and ANXA2 are known to exist as a heterotetrameric complex where an S100A10 dimer resides in the center of the complex, interconnecting 2 Annexin A2 molecules. 44 Similarly, annexin A1 and S100A11 (also called S100C or calgizzarin) interact in a temporal Ca 2C -dependent manner. 48 Several other pairs of annexin and S100 proteins have been discovered and it seems plausible that some S100 proteins can bind several annexins to exert their biological roles.…”

Plasma membrane repair provides a new strategy for targeting metastatic cancer cells

“…Upon Ca 2+ binding annexins bind the negatively charged phospholipids of the membrane to form a ternary complex bridging annexins and membrane together via Ca 2+ [25] . The NH2-terminal region is variable in length and sequence between family members and enables the protein to interact with distinct cytoplasmic partners such as S100 proteins [26] . S100 proteins are small (10-14 kDa), EF-hand-type Ca 2+ -binding proteins that upon Ca 2+ activation exert both intracellular and extracellular functions.…”

“…Several pair of S100-annexin complexes have been identified including the complex of S100A10 and annexin A2 (S100A10-ANXA2) that bind to cytoskeletal components and has been associated with intracellular vesicle fusion [29] . S100A10 and ANXA2 are known to exist as a heterotetrameric complex where an S100A10 dimer resides in the center of the complex, interconnecting two annexin A2 molecules [26] . Similarly, annexin A1 and S100A11 (originally named S100C or calgizzarin) has also been found to interact in a temporal Ca 2+ -dependent manner [30] .…”

“…The majority of the protein family members form symmetric noncovalent homodimers, a feature that is exclusive to the S100 proteins within the EF-hand family of calcium binding proteins [28] . These proteins undergo a profound calcium-induced structural conformation exposing a hydrophobic domain that can interact with the NH2-terminal region of some annexins such as ANXA1 and ANXA2 [26] . This interaction facilitates close apposition of adjacent phospholipid membranes and promotes membrane fusion events [19] .…”