PROSITE documentation PDOC00195
Annexin repeat signature and profile


Annexins [1,2,3,4,5,6,7,8] are a group of calcium-binding proteins that associate reversibly with membranes. They bind to phospholipid bilayers in the presence of micromolar free calcium concentration. The binding is specific for calcium and for acidic phospholipids. Annexins have been claimed to be involved in cytoskeletal interactions, phospholipase inhibition, intracellular signaling, anticoagulation, and membrane fusion. Annexins are widely distributed among eukaryotes but largely absent in prokaryotes and yeast. They are classified according to the evolutionary divisions of the eukaryotes into five families: A (ANXA, vertebrates, including humans), B (ANXB, invertebrates), C (ANXC, fungi), D (ANXD, true plants), E (ANXE, protists).

Each of these proteins consist of a unique N-terminal domain followed by four or eight copies (in annexin A6) of a conserved segment of approximately 70 residues. The tertiary structure of annexins is evolutionary conserved; a single molecule resembles a slightly curved disk with the calcium and phospholipid-binding sites located on the more convex surface and the more concave surface facing the cytoplasm. Each single annexin repeat (sometimes known as an 'endonexin fold') is comprised of five α-helices(A-E) (see <PDB:1AVR>). Four of them (A, B, D and E) are arranged parallel and form a tightly packed helix-loop-helix bundle. In contrast, helix C is almost perpendicular and covers the remaining four on the surface. Each of the repeats has the potential to have a type II Ca(2+)-binding bipartite motif, located on two different α-helices (GxGT-(38-40 residues)-D/E), but typically some of them are non-functional. The core of the helix bundle is composed largely of hydrophobic residues, while hydrophilic residues are exposed on the surface of the protein and between the repeats. The N-terminal domain of variable length, amino acid composition, and determinants of hydrophobicity plays an important role in mediating the interaction of annexins with other intracellular protein partners, such as those of the S100 family cytoplasmic proteins [7,8,9].

The proteins known to belong to the annexin family are listed below:

  • Annexin I (Lipocortin 1) (Calpactin 2) (p35) (Chromobindin 9).
  • Annexin II (Lipocortin 2) (Calpactin 1) (Protein I) (p36) (Chromobindin 8).
  • Annexin III (Lipocortin 3) (PAP-III).
  • Annexin IV (Lipocortin 4) (Endonexin I) (Protein II) (Chromobindin 4).
  • Annexin V (Lipocortin 5) (Endonexin 2) (VAC-α) (Anchorin CII) (PAP-I).
  • Annexin VI (Lipocortin 6) (Protein III) (Chromobindin 20) (p68) (p70). This is the only known annexin that contains 8 (instead of 4) repeats.
  • Annexin VII (Synexin).
  • Annexin VIII (Vascular anticoagulant-β) (VAC-β).
  • Annexin IX from Drosophila.
  • Annexin X from Drosophila.
  • Annexin XI (Calcyclin-associated annexin) (CAP-50).
  • Annexin XII from Hydra vulgaris.
  • Annexin XIII (Intestine-specific annexin) (ISA).
  • α-Giardins from Giardia intestinalis, primitive homologues of annexins [10,11,12].

The signature pattern for this domain spans positions 9 to 61 of the repeat and includes the only perfectly conserved residue (an arginine in position 22). We also developed a profile which covers the entire annexin repeat.

Last update:

June 2019 / Text revised; profile added.


Technical section

PROSITE methods (with tools and information) covered by this documentation:

ANNEXIN_2, PS51897; Annexin repeat profile  (MATRIX)

ANNEXIN_1, PS00223; Annexin repeat signature  (PATTERN)


1AuthorsRaynal P. Pollard H.B.
TitleAnnexins: the problem of assessing the biological role for a gene family of multifunctional calcium- and phospholipid-binding proteins.
SourceBiochim. Biophys. Acta 1197:63-93(1994).
PubMed ID8155692

2AuthorsBarton G.J. Newman R.H. Freemont P.S. Crumpton M.J.
TitleAmino acid sequence analysis of the annexin super-gene family of proteins.
SourceEur. J. Biochem. 198:749-760(1991).
PubMed ID1646719

3AuthorsBurgoyne R.D. Geisow M.J.
TitleThe annexin family of calcium-binding proteins. Review article.
SourceCell Calcium 10:1-10(1989).
PubMed ID2659190

4AuthorsHaigler H.T. Fitch J.M. Jones J.M. Schlaepfer D.D.
TitleTwo lipocortin-like proteins, endonexin II and anchorin CII, may be alternate splices of the same gene.
SourceTrends Biochem. Sci. 14:48-50(1989).
PubMed ID2539661

5AuthorsKlee C.B.
TitleCa2+-dependent phospholipid- (and membrane-) binding proteins.
SourceBiochemistry 27:6645-6653(1988).
PubMed ID2973805

6AuthorsSmith P.D. Moss S.E.
TitleStructural evolution of the annexin supergene family.
SourceTrends Genet. 10:241-246(1994).
PubMed ID8091504

7AuthorsMirsaeidi M. Gidfar S. Vu A. Schraufnagel D.
TitleAnnexins family: insights into their functions and potential role in pathogenesis of sarcoidosis.
SourceJ. Transl. Med. 14:89-89(2016).
PubMed ID27071553

8AuthorsKonopka-Postupolska D. Clark G.
TitleAnnexins as Overlooked Regulators of Membrane Trafficking in Plant Cells.
SourceInt. J. Mol. Sci. 18:0-0(2017).
PubMed ID28422051

9AuthorsHuber R. Roemisch J. Paques E.-P.
TitleThe crystal and molecular structure of human annexin V, an anticoagulant protein that binds to calcium and membranes.
SourceEMBO J. 9:3867-3874(1990).
PubMed ID2147412

10AuthorsFiedler K. Simons K.
TitleAnnexin homologues in Giardia lamblia.
SourceTrends Biochem. Sci. 20:177-178(1995).
PubMed ID7610478

11AuthorsMorgan R.O. Fernandez M.-P.
TitleMolecular phylogeny of annexins and identification of a primitive homologue in Giardia lamblia.
SourceMol. Biol. Evol. 12:967-979(1995).
PubMed ID8524049

12AuthorsWeeratunga S.K. Osman A. Hu N.-J. Wang C.K. Mason L. Svaerd S. Hope G. Jones M.K. Hofmann A.
TitleAlpha-1 giardin is an annexin with highly unusual calcium-regulated mechanisms.
SourceJ. Mol. Biol. 423:169-181(2012).
PubMed ID22796298

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