Structure of the human lipid-gated cation channel TRPC3.
Structure of the human lipid-gated cation channel TRPC3.
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作者：
Fan C;Choi W;Sun W;Du J;Lü W
TRPC通道在钙库操纵的钙进入和钙稳态中起关键作用，并且它们与人类疾病如神经退行性疾病、心脏肥大和脊髓小脑共济失调有关。我们提出了一个结构的全长人TRPC 3，脂质门控TRPC成员，在脂质占据，关闭状态在3.3埃。TRPC 3在第一个跨膜螺旋之前有四个肘状的膜折返螺旋。TRP螺旋垂直于孔衬S6，因此与孔衬S6分离，表明与其他TRP亚家族通道不同的门控机制。第三跨膜螺旋S3非常长，形成独特的跨膜结构域，并构成可以用作外部刺激传感器的细胞外结构域。我们确定了两个脂质结合位点，一个夹在前S1肘和S4-S5接头之间，另一个靠近离子传导孔，TRPC家族保守的LWF基序位于那里。
The TRPC channels are crucially involved in store-operated calcium entry and calcium homeostasis, and they are implicated in human diseases such as neurodegenerative disease, cardiac hypertrophy, and spinocerebellar ataxia. We present a structure of the full-length human TRPC3, a lipid-gated TRPC member, in a lipid-occupied, closed state at 3.3 Angstrom. TRPC3 has four elbow-like membrane reentrant helices prior to the first transmembrane helix. The TRP helix is perpendicular to, and thus disengaged from, the pore-lining S6, suggesting a different gating mechanism from other TRP subfamily channels. The third transmembrane helix S3 is remarkably long, shaping a unique transmembrane domain, and constituting an extracellular domain that may serve as a sensor of external stimuli. We identified two lipid-binding sites, one being sandwiched between the pre-S1 elbow and the S4-S5 linker, and the other being close to the ion-conducting pore, where the conserved LWF motif of the TRPC family is located.