Calcium Unified: Understanding How Calcium's Atomic Properties Impact Human Health

Abstract

Calcium plays a major role in all cellular functions, and its regulation is important in all aspects of human health. This key role calcium plays in cell function can be traced to its unique molecular coordination geometry, which is often overlooked in understanding calcium function. In this review, we integrate calcium's ability to form various complexes with proteins and small molecules with its role as a key signaling atom. We argue that calcium's ability to vary its coordination structures, compared to magnesium's rigid geometry, explains its importance in biological functions. By examining calcium-mediated proteins, such as those containing EF-hand domains and those that assemble and stabilize the extracellular matrix in tissue organization, we demonstrate how calcium's varied geometric coordination serves as both a signaling molecule and a regulator of physiological homeostasis.

Keywords: basic sciences; biomedical education; calcium; calcium-mediated tensegrity; cell signaling; coordination geometry; extracellular matrix; tensegrity.

Figure 1

(Left)—A geometric architectural system composed of triangulated rigid elements that distribute stress across the structure, enabling lightweight yet highly stable designs through optimized load-bearing geometry. (Right)—A diagram of a cube where the internal rods generate a force opposite to the outside lines resulting in a stable cubic structure.

Figure 2

Prestressed (before loading) tensegrity structure that uses a triangulated or modular network of tension elements to stabilize isolated compression components, distributing mechanical forces through a balance of continuous tension and discontinuous compression.

Figure 3

The octahedron represents one of the primary coordination geometries for Ca²⁺ ions in biological systems. This Platonic solid consists of 6 coordination points arranged symmetrically around the central calcium ion, with each point equidistant from the center. The resulting structure has 8 triangular faces, creating perfect triangulation at each face.

Figure 4

Different calcium coordination geometries found in proteins where calcium ions are in blue. These different coordination states can easily shift depending on the number and distance of available ligands. While calcium (blue ball) often forms octahedral (6-coordinate) complexes, its larger ionic radius and coordination flexibility allow it to accommodate 7–8 ligands (orange balls) in arrangements such as the pentagonal bipyramid.

Figure 5

The EF-hand calcium-binding motif. (Left) The structural arrangement shows two alpha helices (E and F) connected by a calcium-binding loop. Specific amino acid residues position oxygen atoms to precisely coordinate the calcium ion. (Right) The hand-like structure where helix E represents the forefinger (yellow), the calcium-binding loop forms the middle finger (orange), and helix F forms the thumb (purple), with calcium binding in the “palm” region. (Adapted from Kretsinger, [25]).

Figure 6

Cartoon showing the scales of calcium impact from ECM in tissues, to cells to calcium coordination complexes.

Figure 7

Posterior view of the human quadriceps femoris group, preserved as an integrated fascial-muscular continuum, revealing collagen decussation and the architectural substrate for tensegral force transmission and calcium-responsiveness. This bespoke dissection highlights the posterior fascial interface of the quadriceps muscle group, with the epimysial and intermuscular fascial layers retained en bloc. The image reveals a striking decussation of collagen fibers, suggesting not only mechanical anisotropy but also a directional tuning of load transmission consistent with tensegrity principles. These criss-crossing fibers reflect a living architecture in which prestress and tissue stiffness are not uniform but vary in response to dynamic functional demands.