Fix in place

Aurora A — an oncogenic serine/threonine protein kinase — is important in cell-cycle progression, and early in mitosis it's required for mitotic spindle assembly. It's activated by the microtubule-associated protein TPX2, which also localizes Aurora A to spindle microtubules, and by phosphorylation. Despite its importance in cell division and cancer, the mechanism of Aurora-A activation has remained unclear. Now though, in Molecular Cell, Conti and colleagues provide new insights by describing the crystal structures of phosphorylated human Aurora A alone and in complex with the minimal activating domain of TPX2.

Comparing the structure of phosphorylated TPX2-bound Aurora A with other kinases showed that it closely matches the active conformation of kinases. In this structure, the 'activation segment' of Aurora A, which contains the crucial phosphothreonine, is in a conformation that is competent for substrate binding. However, in the absence of TPX2, although the overall structure of phosphorylated Aurora A remains very similar, the activation segment adopts an inactive conformation, in which the crucial phosphothreonine is accessible to deactivating phosphatases. So, although TPX2 binding triggers no global conformational change in Aurora A, it pulls on the activation segment using a lever-arm-like mechanism, which moves the phosphothreonine into a buried position and fixes the active conformation in place. And, as the intermolecular interaction between Aurora A and TPX2 resembles the intramolecular interaction of the catalytic core of cAMP-dependent protein kinase with its flanking extensions, this mechanism could be a common theme in kinase regulation. REFERENCE Bayliss, R. et al. Structural basis of Aurora-A activation by TPX2 at the mitotic spindle. Mol. Cell 12, 851–862 (2003)

Getting a grip on GRIP

Four golgins — large coiled-coil proteins that have functions in Golgi structure and vesicle traffic — are targeted to the trans-Golgi membrane by their GRIP domain. This targeting is mediated by GRIP binding to the Arf-like (Arl) GTPase Arl1, which is also Golgi localized. But, what is the molecular basis of this targeting? Munro and colleagues now provide clues in Molecular Cell, by describing the 1.7-Å-resolution crystal structure of human Arl1-GTP in complex with the GRIP domain of the human golgin-245.

In the structure, the GRIP domains form dimers and each monomer contains three anti-parallel α-helices arranged in an S shape. One face of the monomer is involved in dimer formation, while the opposite face binds Arl1. So, each GRIP homodimer binds two Arl-GTPs, and it does this using two α-helices from each monomer. A comparison of this structure with other GTPase–α-helical-effector complexes indicates that, despite the lack of sequence and topology conservation, this recognition of a pair of α-helices might be a common structural basis for effector binding. The bivalent interaction is, however, unique to the Arl1-GTP–GRIP complex, and this interaction might be a way to increase the residence time of this complex on the Golgi membrane. The structure also indicates how this complex might interact with Golgi membranes — through the amino-terminal myristoyl group of each Arl1 and the carboxy-terminal tail of each GRIP. REFERENCE Panic, B. et al. Structural basis for Arl1-dependent targeting of homodimeric GRIP domains to the Golgi apparatus. Mol. Cell 12, 863–874 (2003)