Structure Watch

A constricting girdle

Electrical signalling between nerve and muscle cells is controlled by the acetylcholine (ACh) receptor (AChR) — a transmitter-gated ion channel. AChR has five subunits (α, α, β, γ or ε, δ), which each contain four predicted transmembrane segments (M1–M4). When ACh binds to the ligand-binding regions of the two α subunits, the cation-selective pore opens. But how does this gating occur? In Nature, Unwin and colleagues now provide insights by describing a 4-Å-resolution model of the closed pore, which was obtained using electron microscopy and crystalline postsynaptic membranes.

The authors found that the pentameric pore has two, mainly separate, structural components: an inner circle of M2 helices that create a tapering path for ions; and an outer shell of M1, M3 and M4 helices that shield the inner circle from the lipids. They also found that the ion-conduction path has three negatively charged rings, which might influence ion transport. Furthermore, they were able to identify the gate of the pore — a constricting hydrophobic girdle in the middle of the lipid bilayer, which is formed by weak interactions between adjacent M2 helices. Finally, this work allowed Unwin and co-workers to propose a model for the AChR gating mechanism. In this model, ACh-induced rotations in the ligand-binding domain of the AchR are transmitted to the girdle through the M2 helices, and these rotations open the pore by breaking the girdle apart. REFERENCE Miyazawa, A., Fujiyoshi, Y. & Unwin, N. Structure and gating mechanism of the acetylcholine receptor pore. Nature 424, 949–955 (2003)

Straight to the core

Muscle contraction is regulated by intracellular Ca²⁺ concentration, and troponin is essential in this regulation. Troponin is composed of three different subunits — a Ca²⁺-binding subunit (TnC), an inhibitory subunit (TnI) and a tropomyosin-binding subunit (TnT) — and, together with tropomyosin, it is located on the actin backbone of muscle thin filaments. Although changes in TnC–TnI interactions are thought to be important for muscle contraction, how troponin–tropomyosin regulates the actomyosin ATPase has remained unclear, because high-resolution structures have only been obtained for small sections of the troponin–tropomyosin–actin complex. However, in Nature, Maéda and colleagues now present the high-resolution crystal structures of Ca²⁺-saturated core domains of human cardiac troponin.

These structures revealed the overall architecture of troponin, and showed that it can be divided into structurally distinct subdomains, the boundaries of which do not coincide with the boundaries of TnC, TnI and TnT. These subdomains are connected by flexible linkers, which make the entire molecule very flexible. However, a coiled-coil that is made up of α-helical regions of TnI and TnT forms part of one rigid asymmetric subdomain called the IT arm, and this subdomain bridges putative tropomyosin-anchoring regions. The structures also indicated that Ca²⁺ binding to the regulatory site of TnC might result in the carboxy-terminal region of TnI being detached from actin — a conformational change that could alter the mobility and/or flexibility of troponin and tropomyosin on actin. REFERENCE Takeda, S., Yamashita, A., Maeda, K. & Maéda, Y. Structure of the core domain of human cardiac troponin in the Ca2+-saturated form. Nature 424, 35–41 (2003)