Ironing out the interaction

Because of its potential insolubility and toxicity, ferric iron (Fe3+) is transported around the vertebrate body bound to transferrin, and two iron-bound transferrins can bind the dimeric transferrin receptor (TFR) to deliver iron to cells. Although the endocytic pathway that is involved in this process is well understood, little is known regarding the molecular details of the TFR–transferrin complex. Now, in Cell, Walz and colleagues describe the use of cryo-electron microscopy and single-particle-averaging techniques to obtain a density map of the human TFR–transferrin complex at sub-nanometre resolution, which is “...an unusually high resolution for single-particle analysis”.

The authors fitted crystal structures of the TFR ectodomain and the N- and C-lobes of transferrin into this map to produce an atomic model of the complex. This model indicates that diferric transferrin and TFR interact in a manner that is different to that proposed by a previous model. Rather than binding to membrane-distal surfaces, the C-lobe interacts with the side of the receptor dimer and the N-lobe extends towards the membrane, binding in the gap between the TFR ectodomain and the membrane surface. In addition, the authors noted that, compared with free diferric transferrin, the N- and C-lobes of bound diferric transferrin have shifted by 9 Å with respect to each other, and they believe that this is an effect of receptor binding. This work has therefore improved our structural understanding both of the TFR–transferrin complex and of the different iron-binding properties of free and receptor-bound transferrin. REFERENCE Cheng, Y. et al. Structure of the human transferrin receptor–transferrin complex. Cell 116, 565–576 (2004)

A depolymerizing motor

Kinesin superfamily proteins (KIFs) generally move along microtubules using the energy of ATP hydrolysis, but middle-motor-domain-type KIFs (KIF-Ms) depolymerize microtubules from their ends. How this depolymerization occurs has been unclear, but Hirokawa and co-workers now report new insights in Cell.

The authors determined the crystal structure of the minimal functional domain of a murine KIF-M (Kif2c) in an ADP-bound form and an ATP-analogue-bound form. They compared these structures to those of other KIFs to identify features that are important for KIF-M function, and identified three main class-specific features. First, the amino-terminal neck forms a long, rigid helical structure that extends out into the interprotofilament groove. This structure targets Kif2c to microtubule ends by preventing tight binding to microtubule side walls and aiding its one-dimensional diffusion. It also destabilizes lateral protofilament interactions. Second, the L2 loop — a long, rigid finger-like structure — can reach the next tubulin subunit when Kif2c is at the curved end of the microtubule and stabilize 'peeling' of the protofilament. Finally, the L8 loop, which can contact microtubules at their curved ends, might trigger ATP hydrolysis. This structural model fits with all the data on KIF-Ms to date, but the authors note that a KIF-M–tubulin-complex structure and single-molecule assays will be needed for confirmation. REFERENCE Ogawa, T. et al. A common mechanism for microtubule destabilizers — M type kinesins stabilize curling of the protofilament using the class-specific neck and loops. Cell 116, 591–602 (2004)