Cautious apoptosis

In This Issue In This Issue Held back by a finger he familiar arm-over-arm kinesin swing was recently challenged by proposals that KIF1A acts as a processive, but monomeric, kinesin motor. The proposal involved a rotation of the motor that, along with a microtubule-binding patch, would bias further movement in one direction. But now Al-Bassam et al. add to the growing evidence that the KIF1A orthologue in worms, Unc104, may function as a dimer, like conventional kinesin (page 743). The monomer, they propose, is instead a regulated form whose full activity is only restored when motors are crowded onto cargo vesicles. The unusual prospect of a monomeric motor, and expression problems that had led to the use of a KIF1A/conventional kinesin hybrid in the earlier work, led the authors to study Unc104. Images obtained by cryo-EM revealed a motor domain with a protruding finger that the group identified as representing two neck helices, paired in parallel. Under other conditions, the finger unfolds (i.e., disappears in the EM), and its helices pair intermolecularly with neck helices from another Unc104 motor. The dimeric motor that is now visible by EM should move vesicle traffic along axons processively. Dimerization would be favored when the motor is at high concentrations on vesicle cargo surfaces. But more sparsely spaced Unc104 may stay monomeric because the two neck helices pair with each other. Al-Bassam et al. prevent this inhibitory pairing, and thus the formation of the finger, by T Cautious apoptosis t is not easy to convince sympathetic neurons to commit suicide. Potts et al. (page 789) now show that a caspase inhibitor called XIAP acts as a safety brake so that these terminally differentiated cells do not take the death decision too lightly. Earlier studies established that injection of cytochrome c , which is normally released from mitochondria to activate caspases and thus apoptosis, can kill most cell types but not sympathetic neurons. This resistance can be overcome by coinjection with excess Smac, which shuts down caspase inhibitors including XIAP. Potts et al. now show that cells lacking XIAP no longer need Smac, and succumb to cytochrome c injection alone. This clean result from a single gene deletion was surprising because there are a number of XIAP-like inhibitors, or IAPs, I deleting a hinge between the two helices. This deleted protein can move well in vitro, but is a poor replacement for wild-type gene function …