Crystal structure of the platelet glycoprotein Ib(alpha) N-terminal domain reveals an unmasking mechanism for receptor activation

Glycoprotein Ib (GPIb) is a platelet receptor with a critical role in mediating the arrest of platelets at sites of vascular damage. GPIb binds to the A1 domain of von Willebrand factor (vWF-A1) at high blood shear, initiating platelet adhesion and contributing to the formation of a thrombus. To investigate the molecular basis of GPIb regulation and ligand binding, we have determined the structure of the N-terminal domain of the GPIb(alpha) chain (residues 1-279). This structure is the first determined from the cell adhesion/signaling class of leucine-rich repeat (LRR) proteins and reveals the topology of the characteristic disulfide-bonded flanking regions. The fold consists of an N-terminal beta-hairpin, eight leucine-rich repeats, a disulfide-bonded loop, and a C-terminal anionic region. The structure also demonstrates a novel LRR motif in the form of an M-shaped arrangement of three tandem beta-turns. Negatively charged binding surfaces on the LRR concave face and anionic region indicate two-step binding kinetics to vWF-A1, which can be regulated by an unmasking mechanism involving conformational change of a key loop. Using molecular docking of the GPIb and vWF-A1 crystal structures, we were also able to model the GPIb.vWF-A1 complex.

Electrical neuroimaging in the time domain

A publication entitled “A default mode of brain function” initiated a new way of looking at functional imaging data. In this PET study the authors discussed the often-observed consistent decrease of brain activation in a variety of tasks as compared with the baseline. They suggested that this deactivation is due to a task-induced suspension of a default mode of brain function that is active during rest, i.e. that there exists intrinsic well-organized brain activity during rest in several distinct brain regions. This suggestion led to a large number of imaging studies on the resting state of the brain and to the conclusion that the study of this intrinsic activity is crucial for understanding how the brain works. The fact that the brain is active during rest has been well known from a variety of EEG recordings for a very long time. Different states of the brain in the sleep–wake continuum are characterized by typical patterns of spontaneous oscillations in different frequency ranges and in different brain regions. Best studied are the evolving states during the different sleep stages, but characteristic EEG oscillation patterns have also been well described during awake periods (see Chapter 1 for details). A highly recommended comprehensive review on the brain's default state defined by oscillatory electrical brain activities is provided in the recent book by György Buzsaki, showing how these states can be measured by electrophysiological procedures at the global brain level as well as at the local cellular level.