Crystal structure of the signaling helix coiled-coil domain of the beta1 subunit of the soluble guanylyl cyclase.
Crystal structure of the signaling helix coiled-coil domain of the beta1 subunit of the soluble guanylyl cyclase.
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DOI：
10.1186/1472-6807-10-2
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发表时间：
2010-01-27
影响因子：
--
通讯作者：
van den Akker F
中科院分区：
文献类型：
--
作者：
Ma X;Beuve A;van den Akker F
可溶性鸟苷酸环化酶 (sGC) 是一种异二聚体酶，一氧化氮激活后，会刺激第二信使 cGMP 的产生。每个 sGC 亚基包含四个结构域，其中三个用于异二聚化：H-NOXA/H-NOBA 结构域、卷曲螺旋结构域 (CC) 和催化鸟苷酸环化酶结构域。 CC 结构域先前被认为是称为信号传导螺旋 (S-helix) 家族的更大 CC 家族的一部分。 sGC 的同二聚体也已被观察到，但没有功能活性，但可能是暂时的，等待其预期的异二聚体伙伴。为了研究CC S螺旋区域的结构，我们结晶并确定了包含残基348-409的sGCβ1亚基的CC结构域的结构。晶体结构被细化至 2.15 Å 分辨率。 sGCβ1的CC结构揭示了由CC二聚体的二聚体组成的四聚体排列。每个单体由一个长α-螺旋、一个靠近残基P399的转角和一个短的第二个α-螺旋组成。 CC 结构还提供了有关 sGC 同二聚体如何不像（功能上）活性异二聚体稳定的见解，因为它可能在螺旋间盐桥形成中发挥作用。该结构还深入了解了参与二聚化的残基。此外，CC 区域还已知膜和可溶性鸟苷酸环化酶中存在许多先天性和人为突变，这些影响功能的突变已被映射到 CC 结构上。这种突变分析不仅表明某些二聚化残基位置的重要性，而且对于可能与相邻结构域相互作用的 CC 二聚体的其他面也具有重要作用。我们的结果也超出了鸟苷酸环化酶的范围，因为据我们所知，CC 结构是第一个 S 螺旋结构，并且可作为所有包含 S 螺旋的家族成员的模型。
The soluble guanylyl cyclase (sGC) is a heterodimeric enzyme that, upon activation by nitric oxide, stimulates the production of the second messenger cGMP. Each sGC subunit harbor four domains three of which are used for heterodimerization: H-NOXA/H-NOBA domain, coiled-coil domain (CC), and catalytic guanylyl cyclase domain. The CC domain has previously been postulated to be part of a larger CC family termed the signaling helix (S-helix) family. Homodimers of sGC have also been observed but are not functionally active yet are likely transient awaiting their intended heterodimeric partner. To investigate the structure of the CC S-helix region, we crystallized and determined the structure of the CC domain of the sGCβ1 subunit comprising residues 348-409. The crystal structure was refined to 2.15 Å resolution. The CC structure of sGCβ1 revealed a tetrameric arrangement comprised of a dimer of CC dimers. Each monomer is comprised of a long a-helix, a turn near residue P399, and a short second a-helix. The CC structure also offers insights as to how sGC homodimers are not as stable as (functionally) active heterodimers via a possible role for inter-helix salt-bridge formation. The structure also yielded insights into the residues involved in dimerization. In addition, the CC region is also known to harbor a number of congenital and man-made mutations in both membrane and soluble guanylyl cyclases and those function-affecting mutations have been mapped onto the CC structure. This mutant analysis indicated an importance for not only certain dimerization residue positions, but also an important role for other faces of the CC dimer which might perhaps interact with adjacent domains. Our results also extend beyond guanylyl cyclases as the CC structure is, to our knowledge, the first S-helix structure and serves as a model for all S-helix containing family members.
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