How Leiomodin and Tropomodulin use a common fold for different actin assembly functions.
How Leiomodin and Tropomodulin use a common fold for different actin assembly functions.
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DOI：
10.1038/ncomms9314
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发表时间：
2015-09-15
影响因子：
16.6
通讯作者：
Dominguez R
中科院分区：
文献类型：
--
作者：
Boczkowska M;Rebowski G;Kremneva E;Lappalainen P;Dominguez R
蛋白质如何共享一个共同的折叠进化出不同的功能是生物学中的一个基本问题。原胞调节蛋白（Tmods）是典型的肌动蛋白丝尖端帽蛋白，而它们的同系物，Leiomodins（Lmods），是强大的丝成核剂。我们发现，Tmods和Lmods不竞争生化，并显示类似的，但不同的定位在肌节。Tmods和Lmods的多肽链沿着发生的变化巧妙地调整了它们的功能，使之适合于加帽与成核。Tmods具有交替的原肌球蛋白（TM）和肌动蛋白结合位点（TMBS 1，ABS 1，TMBS 2和ABS 2）。Lmods还含有C-末端延伸，其特征在于肌动蛋白结合WH 2结构域。出乎意料的是，Tmods和Lmods的不同活性并不源于Lmods特异性延伸。相反，Lmods的成核依赖于两个主要的适应-Tmods中存在的尖端帽元件的丢失和高度保守的ABS 2的专门化，用于招募两个或更多个肌动蛋白亚基。WH 2结构域在成核中仅起辅助作用。 平滑肌蛋白和原酸调节蛋白是相关的，但具有不同的功能;分别是肌动蛋白丝成核和尖端封端。在这里，作者使用结构，生物化学和细胞方法来展示这些不同的活动是如何基于共同的蛋白质折叠进化的。
How proteins sharing a common fold have evolved different functions is a fundamental question in biology. Tropomodulins (Tmods) are prototypical actin filament pointed-end-capping proteins, whereas their homologues, Leiomodins (Lmods), are powerful filament nucleators. We show that Tmods and Lmods do not compete biochemically, and display similar but distinct localization in sarcomeres. Changes along the polypeptide chains of Tmods and Lmods exquisitely adapt their functions for capping versus nucleation. Tmods have alternating tropomyosin (TM)- and actin-binding sites (TMBS1, ABS1, TMBS2 and ABS2). Lmods additionally contain a C-terminal extension featuring an actin-binding WH2 domain. Unexpectedly, the different activities of Tmods and Lmods do not arise from the Lmod-specific extension. Instead, nucleation by Lmods depends on two major adaptations—the loss of pointed-end-capping elements present in Tmods and the specialization of the highly conserved ABS2 for recruitment of two or more actin subunits. The WH2 domain plays only an auxiliary role in nucleation. Leiomodins and Tropomodulins are related, but have different functions; actin filament nucleation and pointed end capping, respectively. Here, the authors use structural, biochemical and cellular approaches to show how these different activities have evolved based on a common protein fold.