Annexins and Membrane Fusion - Fusion of Biological Membranes and Related Problems - page 118

8. CONCLUSION AND OUTLOOK
Many of the properties of proteins involved in NSF, SNAPs, SNAREs-
dependent vesicle transport and membrane fusion machinery (Zheng and
Bobich, 1998) are shared by annexins. Annexins bind to negatively-charged
phospholipids in a Ca 2+ -dependent manner, as does synaptotagmin. Annex-
ins bind to vesicular membranes (as do synaptobrevin, synaptophysin
and synaptotagmin) and the plasma membrane (as do syntaxin and
SNAP-25). They bind both to the plasma membrane and cytoskeletal ele-
ments (synapsin I). Annexins tend to self association and polymerize (as do
synaptotagmin, synaptophysin), bind GTP (as do rabs), bind and bundle F-
actin (also shown for synapsin I), are involved in membrane organization
(PEP proteins) and form membrane channels (as does synaptophysin), to
name but a few parallels. Besides the ubiquity of the NSF, SNAP S , SNAREs-
dependent exocytotic machinery, NSF-independent vesicle transport and
fusion pathways have been identified (Gerke and Moss, 1997). One such
NSF-independent mechanism was shown to involve annexin XIIIb in
MDCK cells (Lafont et al., 1998). This raises the possibility, that annexins
provide a specialized exocytotic pathway that works in parallel to other
mechanisms such as NSF-dependent exocytosis. Alternatively, the interac-
tion of the C-terminus of annexin I with synaptotagmin appears to support
FIGURE 10. Putative roles of annexins in vesicle trafficking and secretion. In unstimulated
chromaffin cells, a large fraction of annexin II is present in monomeric form in the cytosol (1).
Upon stimulation and rise of intracellular free Ca 2+ due to Ca 2+ -influx (2), annexin II translo-
cates to the cell cortex and forms a (Ca 2+ -independent) heterotetrameric complex with p11
(3), which is already present in the submembraneous area before stimulation. The annexin
II 2 /p11 2 -heterotetramer crosslinks and thereby aggregates secretory vesicles (4), anchors secre-
tory vesicles to the plasma membrane (3, and causes F-actin bundling (6). The latter leads to
disassembly of the cortical actin web, which until then prevented approach of chromaffin gran-
ules (7). The granules can now move into close proximity of the plasma membrane. There,
protein kinase C phosphorylation of annexin II induces disassembly of the heterotetramer.
Phosphorylated annexin II then induces fusion of the chromaffin granule with the plasma
membrane (8). Annexins may also be involved in vesicular transport along the cytoskeleton,
possibly by forming an adaptor protein for apical transport carriers to motor proteins, as sug-
gested for annexin XIIIb in MDCK cells (Lafont et al., 1998) (9). Annexin VI is localized in
the plasma membrane undercoat and upon contact with chromaffin granules releases intra-
granular Ca 2 +, thereby augmenting the cytosolic Ca 2+ signal (10). Furthermore, annexins may
be involved in the organization of membrane rnicrodornains of specific lipid composition, e.g.
PIP 2 /cholesterol-rich domains (11), stabilization (12) or destabilization of fusion membranes
(13), and regulation of PKC (14) and/or elements of the NSF-SNAP-SNARE fusion machin-
ery (15), as discussed in the text. Some annexins, in particular annexin V and VI may also
display a regulatory effect on the proposed functions of other annexin-family members (not
shown).