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首页> 外文期刊>Journal of Molecular Biology >Small-angle X-ray scattering reveals the N-terminal domain organization of cardiac myosin binding protein C
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Small-angle X-ray scattering reveals the N-terminal domain organization of cardiac myosin binding protein C

机译：小角度X射线散射揭示了心肌肌球蛋白结合蛋白C的N末端结构域

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摘要

Myosin binding protein C (MyBP-C) is a multidomain accessory protein of striated muscle sarcomeres. Three domains at the N-terminus of MyBP-C (Cl-m-C2) play a crucial role in maintaining and modulating actomyosin interactions. The cardiac isoform has an additional N-terminal domain (CO) that is postulated to provide a greater level of regulatory control in cardiac muscle. We have used small-angle X-ray scattering, ab initio shape restoration, and rigid-body modeling to determine the average shape and spatial arrangement of the four N-terminal domains of cardiac MyBP-C (C0C2) and a three-domain variant that is analogous to the N-terminus of the skeletal isoform (C1C2). We found that the domains of both proteins are tandemly arranged in a highly extended configuration that is sufficiently long to span the interfilament cross-bridge distances in vivo and, hence, be poised to modulate these interactions. The average spatial organization of the C1, m, and C2 domains is not significantly perturbed by the removal of the cardiac-specific CO domain, suggesting that the interdomain interfaces, while relatively small in area, have a degree of rigidity. Modeling the C0C2 and C1C2 scattering data reveals that the structures of the C0 and m domains (also referred to as the 'MyBP motif') are compact and have dimensions that are consistent with the immunoglobulin fold superfamily of proteins. Sequence analysis, homology modeling, and circular dichroism experiments support the conclusion that the previously undetermined structures of these domains can be characterized as having an immunoglobulin-like fold. Atomic models using the known NMR structures for C1 and C2 as well as homology models for the C0 and m domains provide insights into the placement of conserved serine residues of the m domain that are phosphorylated in vivo and cause a change in muscle fiber contraction by abolishing interactions with myosin. (C) 2008 Elsevier Ltd. All rights reserved.
机译：肌球蛋白结合蛋白C（MyBP-C）是横纹肌肉瘤的多结构域辅助蛋白。 MyBP-C（C1-m-C2）N末端的三个域在维持和调节肌动球蛋白相互作用中起着至关重要的作用。心脏同工型具有一个额外的N末端结构域（CO），假定该结构可在心肌中提供更高水平的调节控制。我们已经使用小角度X射线散射，从头算形状恢复和刚体建模来确定心脏MyBP-C（C0C2）和三个结构域变体的四个N末端结构域的平均形状和空间排列类似于骨骼亚型（C1C2）的N端。我们发现这两种蛋白的域以高度延伸的构型串联排列，该构型足够长以跨越体内的丝间跨桥距离，因此可以调节这些相互作用。 C1，m和C2域的平均空间组织不会因去除心脏特异性CO域而受到明显干扰，这表明域间界面虽然面积相对较小，但具有一定程度的刚性。对C0C2和C1C2散射数据进行建模后发现，C0和m结构域的结构（也称为“ MyBP基序”）是紧凑的，其尺寸与蛋白质的免疫球蛋白折叠超家族一致。序列分析，同源性建模和圆二色性实验支持以下结论：这些结构域先前未确定的结构可以表征为具有免疫球蛋白样折叠。使用已知的C1和C2 NMR结构的原子模型以及C0和m结构域的同源性模型，可以深入了解m结构域中保守的丝氨酸残基的位置，这些残基在体内被磷酸化并通过消除而导致肌肉纤维收缩的改变与肌球蛋白的相互作用。 （C）2008 Elsevier Ltd.保留所有权利。

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