Consequences of a traffic jam

In This Issue In This Issue trophin, a member of the spectrin superfamily of actin-binding proteins ubiquitously expressed in human cells, helps link the actin cytoskeleton to the extracellular matrix. Galkin et al. report on page 231 that a newly developed image analysis method identifies two different modes of utrophin binding to F-actin. The findings contradict earlier studies on utrophin–actin interactions and provide a clearer explanation of how relatively few proteins may generate the diverse interactions and structures seen in the actin cytoskeleton. The amino-terminal domain of utrophin contains a tandem pair of calponin homology (CH) domains, which are important for binding to actin. Unfortunately, disorder in binding and the variable twist of F-actin obscure the three-dimensional structure of utrophin–actin complexes seen under the electron microscope, making detailed studies problematic. Galkin et al. tackled this problem with their recently developed image analysis algorithm, which can separate classes of polymorphic structures that are indistinguishable by traditional techniques. First reported last year, the new method is rapidly gaining acceptance. It is now being used to study several other actin-binding proteins, as well as protein–DNA interactions during recombination. Previous work identified only one type of utrophin binding to actin, but the new study shows that the utrophin actin-binding U Consequences of a traffic jam dentifying the genetic basis of a disease is only a small step toward understanding its pathogenesis, as Simons et al. clearly demonstrate on page 327. The dysmyelinating condition Pelizaeus-I Merzbacher disease (PMD) is caused by duplication or overexpression of the myelin proteolipid protein (PLP) gene, but it was not clear if excess PLP caused dysmyelination directly or indirectly. Simons et al. characterized the changes in intracellular trafficking caused by PLP overexpression in three systems. Their findings help PLP (green) gets misrouted to late endosomes (red). define a pathway that may transport myelin rafts in oligodendrocytes, and suggest that PLP overexpression causes PMD by a multistep, indirect mechanism. The authors examined BHK cells, oligodendrocytes, and transgenic mice Utrophin gets a new look Utrophin (green) can bind to actin (light blue) in two different modes. authors propose that PLP overexpression saturates the myelin raft transport pathway, causing the surplus PLP to be routed to the degradative compartment. This rerouting also causes the misdirection of cholesterol, and eventually other raft components, to the late endosome/lysosome. Thus PLP overexpression may trigger a chain of events that could trap myelin lipids, impair normal trafficking …