Collagen Alpha 1(XI) Amino-Terminal Domain Modulates Type I Collagen Fibril Assembly.

IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Abu Sayeed Chowdhury, Julia Thom Oxford
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引用次数: 0

Abstract

The amino-terminal domain of collagen α1(XI) plays a key role in controlling fibrillogenesis. However, the specific mechanisms through which various isoforms of collagen α1(XI) regulate this process are not fully understood. We measured the kinetics of collagen type I self-assembly in the presence of specific collagen α1(XI) isoforms. Molecular dynamics simulations, protein-protein docking studies, and molecular mechanics Poisson-Boltzmann surface area were utilized to understand the molecular mechanisms. In vitro, in silico, and thermodynamic studies demonstrated an isoform-specific effect on self-assembly kinetics. Our results indicate isoform-specific differences in the rate constants, activation energy, and free energy of binding. These differences may result from isoform-specific interaction dynamics and modulation of steric hindrance due to the chemically distinct variable regions. We show that isoform A interacts with collagen type I due in part to the acidic variable region, increasing the activation energy of fibril growth while decreasing the rate constant during the growth phase. In contrast, the basic variable region of isoform B may result in less steric hindrance than isoform A. Isoform 0 demonstrated the highest activation energy and the lowest rate constant during the growth phase. Although the presence of isoforms reduced the rate constants for fibril growth, an increase in total turbidity during the plateau phase was observed compared to controls. Overall, these results are consistent with collagen α1(XI) NTD isoforms facilitating fibrillogenesis by increasing the final yield by reducing the rate of the lag and/or growth phases, while extending the duration of the growth phase.

胶原α 1(XI)氨基末端结构域调节I型胶原原纤维组装。
胶原α1(XI)的氨基末端结构域在控制纤维形成中起关键作用。然而,胶原α1(XI)的各种异构体调节这一过程的具体机制尚不完全清楚。我们测量了在特定胶原α1(XI)亚型存在下I型胶原自组装的动力学。利用分子动力学模拟、蛋白质-蛋白质对接研究和分子力学泊松-玻尔兹曼表面积来了解分子机制。体外、硅和热力学研究证明了对自组装动力学的异构体特异性影响。我们的研究结果表明,在速率常数、活化能和结合自由能方面存在异构体特异性差异。这些差异可能是由于同工异构体特异性相互作用动力学和由于化学上不同的可变区而引起的位阻调制。我们发现异构体A与I型胶原的相互作用部分是由于酸性可变区,增加了原纤维生长的活化能,同时降低了生长阶段的速率常数。相比之下,异构体B的基本可变区可能比异构体a产生更小的位阻,异构体0在生长阶段表现出最高的活化能和最低的速率常数。虽然同种异构体的存在降低了原纤维生长的速率常数,但与对照组相比,观察到高原阶段总浊度增加。总的来说,这些结果与胶原α1(XI) NTD异构体通过减少滞后期和/或生长阶段的速率增加最终产量,同时延长生长阶段的持续时间,从而促进纤维形成的观点一致。
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来源期刊
Biochemistry Biochemistry
Biochemistry Biochemistry 生物-生化与分子生物学
CiteScore
5.50
自引率
3.40%
发文量
336
审稿时长
1-2 weeks
期刊介绍: Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.
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