Calmodulin binding (left) displaces part of VAMP from cis membranes, but trans membranes then displace calmodulin (right).

Seagar/NAS

Calcium and calmodulin transfer a critical region of the vesicle protein VAMP from donor to target membrane, suggest Luc de Haro, Michael Seagar (INSERM, Marseille, France), and colleagues. The transfer may help to fuse the two membranes together.

VAMP is a v-SNARE: a helical protein sticking out of donor vesicles that zippers up with t-SNAREs on target membranes. Seagar has previously found that a membrane-proximal section of VAMP shows mutually exclusive binding to calmodulin or acidic phospholipids. Interaction with lipids in the donor vesicle membrane may inhibit fusion.

Now, Seagar finds that Ca2+/calmodulin alleviates this inhibition, at least as far as the binding step. Ca2+/calmodulin binds to VAMP-loaded vesicles, and is needed for target membranes to bind to the VAMP on VAMP-loaded vesicles.

The group suggests that the VAMP association with cis membranes is disfavored by a kinking back of the protein, allowing displacement by Ca2+/calmodulin. This interaction (and calmodulin itself) is then displaced by the more straightforward insertion of the VAMP residues into the target membrane.

Thus, Ca2+/calmodulin can unidirectionally transfer a protein between two lipid domains of identical composition. But how important is this for fusion? Ca2+/calmodulin was an early favorite of those looking for a fusion trigger but later fell out of favor when it became clear that inhibitors had pleiotropic effects on numerous kinases and channels. Now, says Seagar, “to say that calmodulin is doing something important in membrane fusion is still to some people saying something heretical.”

Some of those people subscribe to the theory that SNARE proteins can do fusion by themselves. But Seagar points out that several groups have now observed the inhibitory property of the source membrane on SNARE activity. The new results show how Ca2+/calmodulin can overcome this inhibition and perhaps convert it into fusion.

Ca2+/calmodulin is not the whole story. Seagar suggests that it may be an archaic fusion trigger used in yeast and some intracellular trafficking events in mammals. But in the nervous system, where a faster trigger was needed, it may have been superseded by synaptotagmin. ▪

Reference:

de Haro, L., et al.
2004
.
Proc. Natl. Acad. Sci. USA.
101
:
1578
–1583.