The annexins (Annexin A or Anneixin II or Annexin 2) are a family of calcium (CA2+) and phospholipid binding proteins that differ from most other Ca2+ binding proteins in their Ca2+ binding sites. The annexin family Ca2+ binding site has a unique architecture that enables annexin family members to reversibly dock onto the periophery of cellular and/or organellar membranes.
Structure
The basic structural domains of the annexins consist of a variable amino-terminal head domain and a homologous carboxyl domain. The amino-terminal domain contains sites for post translational modification and protein-protein interactions and imparts each annexin with a unique function(s) (Bharadwaj, Int. J. Mol. Sci. 2013). The conserved Ca2+ binding site characteristic of annexin family members is located in the annexin core domain and comprises four annexin repeats, each 70 amino acids long.
Types of Annexin Proteins
Annexin proteins include the following proteins of the annexin family:
Annexin II (lipocortin 2, calpactin 1, protein I, p36, chromobindin 8):
–Structure: As described above for annexins in general, annexin A2 is composed of two major domains, the highly variant amino terminal domain or head region and the conserved carboxyl-terminal core domain. The amino terminal region is the site for post-translational modification as well as ligand and protein interactions, while the carboxyl terminal core region contains binding site for calcium. (Bharadwaj, Int. J. Mol. Sci. 2013).
–Functions:
Ohlfest (US2013/0331546) discloses that annexin II has immunostimulatory properties.
Pryzdial (US2006/0057591) teaches a method for preventing or treating viral infections by inhibiting Annexin 2. Kast 9US2011/0086044) teaches a method for inhibiting and treating HPV infection by administering an agent that inhibit HPV binding to annexin A2 present on the surface of the cells.
Malhotra (Microbes and Infection, 2003, “isolation and characterisation of potential respiratory syncytial virus receptor(s) on epithelial cells” discloses that inhibitors of annexin II could have potential in treating RSV infection.
Annexin III (lipocortin 3, PAP-III):
Annexin IV (lipocortin 4, endonexin I, protein II, chromobindin 4)
Annexin V (lipocortin 5, Endonexin 2, VAC-alpha, Anchroin CII, PAP-I):
–Structure:
–Functions:
Annexin V binds with high affinity to membrane bound phosphatidylserine (PS) molecuels in a Ca2+ dependent manner. Annexin V staining has been a standard pratice for the assessment of apoptosis becasue one o the ealry characteristics of apoptosis is the externalization of PS molecules on cell membranes, which promotes recognition and phagocytic removal. (Li, Bioconjugate Chem 2008, 19, 1684-1688). Elecron crystallography of membrane boudn annexin A5 has demonstrated that annexin A5 molecules can associate with each other via protein-protein interactions. In solution annexin A5 molecules are monoemrs, but upon binding to a PS epxressing membrane they self-assemble into timers followed by the formation of a two-dimensional crystal lattice. (Reutelingsperger, Biochimica et Biophysica Aeta 1783, 2008 953-963).
–Therapeutic applications:
Allison (US 6,962,903) disclsoes methods for preventing arterial or venous thrombosis without increasing hemorrhage by administering a modified annexin V such that its half-life is increased.
–Variants:
Li, (Bioconjugate Chem 2008, 19, 1684-1688) discloses chainging a cysteine in the N-temrinus of Annexin V to a serine in order to elimiate the possibility of modificaiton by thiol-reactive prosthetic conjugationg agents. Reutelingsperger (US 2012/0094895) disclsoes an annexin A5 variant that includes one or more RGD (Arg-Gly-Asp) sequences which is suitable for treating a disease where phagocytosis is a desired effect of treatment such as atheroscelerotic plaque or COPD.
Annexin VI (lipocortin 6, Protein III, Chromobindin 20, p68, p70)
Annexin VII (Synexin)
Annexin VIII (VAC-beta)
Annexin XI (CAP-50)
Annexin XIII (ISA)
Functions
The annexin A 2 subfamily have been shown to associate with diverse sites of actin attachment at cell membranes and to serve as receptors for plasminogen and tissue plasminogen activator, positively modulating the fibrinlytic cascade among other activities.
Complement activation:
Annexin A2 has also been dientified as a component of drusen in monkeys affected with both early and late onset of macular degeneration.
Thurman (US 13/120125) discloses that Annexin A2 can enhance complement activation on cell surfaces by blocking the interaction of factor H with the cell surface and that mice in which Annexin A2 production is blocked display greater complement activation after renal I/R/