Complex construction

There are more than 20 isoforms of Ca2+/calmodulin-dependent protein kinase II (CaMKII) — an oligomeric serine/threonine kinase that is activated by Ca2+-bound calmodulin. CaMKII responds to changes in Ca2+ levels in a complex manner that is presently unclear, but is known to depend on the architecture of this oligomeric assembly. The CaMKII oligomer was thought to be dodecameric (12 subunits). However, the 2.6-Å resolution crystal structure of the association domain of the CaMKII α-isoform, which is described by Kuriyan and colleagues in Molecular Cell, now challenges this view.

The carboxy-terminal association domain of CaMKII is responsible for its oligomerization, and the authors found that CaMKIIα association domains come together to form a tetradecameric assembly. They form a circular hub, which has a central pore and is made up of two seven-membered rings stacked head-to-head. Each of the 14 protomers is wedge-shaped and has a long α-helix at its amino terminus, that extends towards the equatorial plane of the circular structure. As this α-helix links the association domain to the CaMKII kinase domain, it is probable that the kinase domains form a second outer ring around the circular hub, and this complex construction is crucial to allow CaMKII to respond to Ca2+ levels in a complex way. Furthermore, the authors identified a potential peptide-binding pocket in each protomer, which faces the pore's centre and might function as a docking site for proteins that interact with CaMKII. However, the functional significance of this pocket needs to be clarified. REFERENCE Hoelz, A. et al. Crystal structure of a tetradecameric assembly of the association domain of Ca2+/calmodulin-dependent kinase II. Mol. Cell 11, 1241–1251 (2003)

One way to recognize?

Monoubiquitylation functions as a regulatory modification in various cellular processes, and the monoubiquitin signal is transmitted when it interacts with ubiquitin-binding motifs that are found in eukaryotic proteins with varied functions. Although several ubiquitin-binding motifs have been characterized, high-resolution information regarding monoubiquitin-signal recognition is lacking. Now, though, in Cell, Radhakrishnan and co-workers provide new insights.

CUE domains are involved in monoubiquitin and polyubiquitin recognition, and they also facilitate intramolecular monoubiquitylation. So, to further understand how CUE domains recognize ubiquitin, the authors determined the NMR solution structure of the CUE2-1 domain from the yeast Cue2 protein bound to yeast ubiquitin. This structure revealed interactions between CUE2-1 and ubiquitin that involve hydrophobic patches, such as the Leu8-Ile44-Val70 patch on ubiquitin. In addition, the interaction site encompasses Lys48 of ubiquitin — the site of polyubiquitin chain formation. This indicates that the CUE domain might stop polyubiquitin chains forming during monoubiquitin signalling. Comparative modelling showed that the UBA motif ('ubiquitin-associated') might also interact with ubiquitin in this way, so the authors believe that the CUE2-1–ubiquitin structure might “...serve as a paradigm for ubiquitin recognition and signaling by ubiquitin binding proteins”. REFERENCE Kang, R. S. et al. Solution structure of a CUE–ubiquitin complex reveals a conserved mode of ubiquitin binding. Cell 113, 621–630 (2003)