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首页> 外文期刊>Journal of Molecular Biology >Topological frustration in beta alpha-repeat proteins: sequence diversity modulates the conserved folding mechanisms of alpha/beta/alpha sandwich proteins.
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Topological frustration in beta alpha-repeat proteins: sequence diversity modulates the conserved folding mechanisms of alpha/beta/alpha sandwich proteins.

机译：Beta alpha重复蛋白的拓扑受挫：序列多样性调节了alpha / beta / alpha夹心蛋白的保守折叠机制。

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The thermodynamic hypothesis of Anfinsen postulates that structures and stabilities of globular proteins are determined by their amino acid sequences. Chain topology, however, is known to influence the folding reaction, in that motifs with a preponderance of local interactions typically fold more rapidly than those with a larger fraction of nonlocal interactions. Together, the topology and sequence can modulate the energy landscape and influence the rate at which the protein folds to the native conformation. To explore the relationship of sequence and topology in the folding of beta alpha-repeat proteins, which are dominated by local interactions, we performed a combined experimental and simulation analysis on two members of the flavodoxin-like, alpha/beta/alpha sandwich fold. Spo0F and the N-terminal receiver domain of NtrC (NT-NtrC) have similar topologies but low sequence identity, enabling a test of the effects of sequence on folding. Experimental results demonstrated that both response-regulator proteins fold via parallel channels through highly structured submillisecond intermediates before accessing their cis prolyl peptide bond-containing native conformations. Global analysis of the experimental results preferentially places these intermediates off the productive folding pathway. Sequence-sensitive Go-model simulations conclude that frustration in the folding in Spo0F, corresponding to the appearance of the off-pathway intermediate, reflects competition for intra-subdomain van der Waals contacts between its N- and C-terminal subdomains. The extent of transient, premature structure appears to correlate with the number of isoleucine, leucine, and valine (ILV) side chains that form a large sequence-local cluster involving the central beta-sheet and helices alpha2, alpha 3, and alpha 4. The failure to detect the off-pathway species in the simulations of NT-NtrC may reflect the reduced number of ILV side chains in its corresponding hydrophobic cluster. The location of the hydrophobic clusters in the structure may also be related to the differing functional properties of these response regulators. Comparison with the results of previous experimental and simulation analyses on the homologous CheY argues that prematurely folded unproductive intermediates are a common property of the beta alpha-repeat motif.
机译：Anfinsen的热力学假设假设，球形蛋白质的结构和稳定性由其氨基酸序列决定。然而，已知链拓扑会影响折叠反应，因为具有局部相互作用的基序通常比具有较大比例的非局部相互作用的基序折叠得更快。在一起，拓扑和序列可以调节能量格局，并影响蛋白质折叠成天然构象的速率。为了探索以局部相互作用为主的β-α-重复蛋白折叠中序列与拓扑的关系，我们对黄素类毒素样α/β/α三明治折叠的两个成员进行了组合的实验和模拟分析。 Spo0F和NtrC（NT-NtrC）的N末端受体结构域具有相似的拓扑结构，但序列同一性较低，因此可以测试序列对折叠的影响。实验结果表明，这两种应答调节蛋白都通过平行通道折叠，经过高度结构化的亚毫秒级中间体，然后才能进入含有顺式脯氨酰肽键的天然构象。对实验结果的全局分析优先将这些中间体置于生产性折叠途径之外。序列敏感的Go-model模拟得出的结论是，Spo0F中折叠的受挫感（对应于偏离通路的中间体的出现）反映了其N端和C端子域之间的子域内范德华接触的竞争。瞬态，过早结构的程度似乎与异亮氨酸，亮氨酸和缬氨酸（ILV）侧链的数量相关，后者形成一个大的序列局部簇，涉及中央β-折叠和螺旋α2，α3和α4。在NT-NtrC模拟中未能检测到非通路物种可能反映了其相应疏水簇中ILV侧链数量的减少。疏水簇在结构中的位置也可能与这些响应调节剂的不同功能特性有关。与之前对同源CheY进行的实验和模拟分析的结果相比较，认为过早折叠的非生产性中间体是β-α-重复基序的共同特征。

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