The Relevance, Predictability, and Utility of Annexin A5 for Human Physiopathology

Abstract

As an important functional protein molecule in the human body, human annexin A5 (hAnxA5) is widely found in human cells and body fluids. hAnxA5, the smallest type of annexin, performs a variety of biological functions by reversibly and specifically binding phosphatidylserine (PS) in a calcium-dependent manner and plays an important role in many human physiological and pathological processes. The free state hAnxA5 exists in the form of monomers and usually forms a polymer in a specific self-assembly manner when exerting biological activity. This review systematically discusses the current knowledge and understanding of hAnxA5 from three perspectives: physiopathological relevance, diagnostic value, and therapeutic utility. hAnxA5 affects the occurrence and development of many physiopathological processes. Moreover, hAnxA5 can be used independently or in combination as a biomarker of physiopathological phenomena for the diagnosis of certain diseases. Importantly, based on the properties of hAnxA5, many novel drug candidates have been designed and prepared for application in actual medical practice. However, there are also some gaps and shortcomings in hAnxA5 research. This in-depth study will not only expand the understanding of structural and functional relationships but also promote the application of hAnxA5 in the field of biomedicine.

Keywords: human annexin A5; phosphatidylserine (PS); physiopathology; self-assembly.

Figure 1

Schematic representation of the structures of all human annexin class A proteins.

Figure 2

The endocytosis pathway mediated by surface-expressed PS and hAnxA5. Cell surface expression of PS leads to disassembly of the cortical actin network beneath membrane patches exposed to PS. The membrane-facing convex shape of membrane-associated protein A5-trimers and the ability of these trimers to form a two-dimensional lattice drive membrane internalization and bend the membrane patch toward invagination. The invaginated endocytic vesicle membrane structure is closed and wrapped with F-actin, and vesicle membranes are fissioned from the plasma membrane and transported in a microtubule-dependent manner into the cytosol.

Figure 3

The structural features of hAnxA5. (A) Side view (convex face). Calcium atoms are represented as green spheres. Each of the four domains is represented by a different color. (B) Top view. (C) Close view of domain I showing the five helices, the three bound calcium atoms(green spheres), and three bidentate calcium ligands Glu35 (B site), Glu72 (AB site), and Glu78 (DE site). (Protein Data Bank accession number 1AVR).

Figure 4

hAnxA5-based phosphatidylserine-dependent endocytosis for the targeted therapeutic agent. hAnxA5 binds to PS, which is everted on the cell membrane. Then, hAnxA5 forms two-dimensional crystals that bend the plasma membrane. Next, endocytic vesicles form. Finally, vesicles in the plasma membrane are divided by an as-yet unidentified mechanism.