246
Annexins
Chromaffin granule
membrane
Synexin
10
>
[Ca
2
+
]
>
1
µ
M
[Ca
2
+
]
>
10
µ
M
Fig. 3
Hypothesis for the mechanism
of action of synexin (annexin VII) in
promoting intermembrane contacts in a
cell. In the resting cell (top), the Ca
2
+
concentration is less than 1
µ
Mand
synexin is freely soluble. In the
stimulated cell (middle), as the calcium
concentration rises to between 1 and
10
µ
M, synexin attaches to membranes.
When the calcium concentration further
increases above 10
µ
M(perhapsnear
the plasma membrane), synexin
molecules on different membranes
self-associate to bring the membranes
together. [Reproduced from Creutz and
Sterner (1983), with permission.]
in the case of the annexin II heavy chain,
which associates with p10, and annexin XI,
which associates with the small calcium-
binding protein, calcyclin. The N-terminal
domains are also potential regulatory sites
for the rest of the molecule. For example,
cleavage of the N-terminus of the isolated
annexin II heavy chain is necessary for this
protein to aggregate chromaf±n granules
at low levels of calcium. Furthermore, the
calcium sensitivity of membrane aggrega-
tion by such cleaved molecules is strongly
affected by the exact site of cleavage. In
addition, annexins I and II are phos-
phorylated in the N-terminal domain by
tyrosine- or serine-/threonine-speci±c ki-
nases. Phosphorylation of the N-terminus
of annexin I by protein kinase C
blocks
the
ability of this protein to aggregate chro-
maf±n granules, while slightly
enhancing
its ability to bind the granule membrane.
These biochemical observations on the
importance of the annexin N-terminal
structure can be interpreted in terms of
the crystal structure of annexin V. Since
the N-terminus is located on the ‘‘cyto-
plasmic’’ side of the membrane-bound
annexin, it may be in a position to partic-
ipate in annexin–annexin self-association
essential to membrane aggregation. This
may explain why alterations of the tails of
other annexins strongly affect membrane
aggregation but not membrane binding.
Such alterations, resulting from either pro-
teolysis or phosphorylation, may provide
additional mechanisms for cellular control
of these calcium-dependent proteins.
4
Applications
Although the complete breadth and details
of the biological roles of annexins are yet
