Abstract
Ryanodine Receptor Structure: Progress and Challenges
Highlights
Ryanodine-sensitive Ca2ϩ release channels, known as the ryanodine receptors (RyRs),2 are homotetramers of an ϳ550-kDa subunit (Fig. 1) that are resident proteins of intracellular membranes such as the sarcoplasmic/endoplasmic reticulum
The CY region is strikingly empty with numerous distinctive structural domains and intervening cavities that appear suitable for interaction with modulators that bind within the N-terminal regions of RyR (Fig. 1)
The best current maps of RyR1 have resolutions of ϳ10 Å [2, 3], allowing delineation of secondary structure elements in the pore region (Fig. 2A): the helix running across the membrane, the short helix that forms the lumenal entrance of the channel, and helix 3
Summary
The pore is thought to be composed of six to eight TM segments (RyR1 TM1– 8, amino acids (aa) 4277– 4323, 4343– 4363, 4557– 4576, 4637– 4662, 4776 – 4800, 4803– 4825, 4834 – 4854, and 4911– 4935 with aa 4854 – 4911 forming the pore helix and selectivity filter) (Fig. 1A, line 1) [6]. Ludtke et al [2] found a bent pore-lining helix (Fig. 2A) and suggested that the structure is similar to the open MthK channel [8] This raises questions as to whether “kinking” of the inner helix alone, as proposed for Kϩ channels, is adequate to open RyRs. the conformation of the pore-lining helix in the other high resolution RyR1 cryo-EM structure [3] is straight and resembles the closed KcsA channel structure [7]. At the current level of resolution in the three-dimensional structure of RyR, it is not possible to elucidate the number of TM helices
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