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整联蛋白结合序列N端Gly突变对重组胶原蛋白结构和功能的影响

[Effects of Gly mutations N-terminal to the integrin-binding sequence on the structure and function of recombinant collagen].

作者信息

Li Fei, Hou Yuxi, Rao Ben, Liu Xiaoyan, Wang Yaping, Qiu Yimin

机构信息

National Biopesticide Engineering Research Centre, Biopesticide Branch of Hubei Innovation Centre of Agricultural Science and Technology, Hubei Biopesticide Engineering Research Centre, Hubei Academy of Agricultural Sciences, Wuhan 430064, Hubei, China.

School of Life Sciences, Hubei University, Wuhan 430062, Hubei, China.

出版信息

Sheng Wu Gong Cheng Xue Bao. 2025 Apr 25;41(4):1573-1587. doi: 10.13345/j.cjb.240722.

Abstract

Collagen, a vital matrix protein for various tissue and functions in animals, is widely applied in biomaterials. In type Ⅰ collagen, missense mutations of glycine (Gly) in the Gly-Xaa-Yaa triplet of the triple helix are a major cause of osteogenesis imperfecta (OI). Clinical manifestations exhibit marked heterogeneity, spanning a broad disease spectrum from mild skeletal fragility (Type Ⅰ) to severe limb deformities (Type Ⅲ) and perinatal lethal forms (Type Ⅱ). This study utilized recombinant collagen as a model to further elucidate whether Gly→Ala/Val mutations at the N-terminus of the integrin-binding sequence GFPGER affect collagen structure and function, and to explore the underlying mechanisms by which missense mutations impact the biological function of collagen. By introducing Ala and Val substitutions at seven Gly positions N-terminal to the GFPGER sequence, we systematically assessed the effects of these amino acid replacements on the triple-helical structure, thermal stability, integrin-binding ability, and cell adhesion of recombinant collagen. All constructs formed a stable triple-helix structure, with slightly compromised thermal stability. Gly→Val substitutions increased the susceptibility of recombinant collagen to trypsin, which suggested local conformational perturbations in the triple helix. In addition, Gly→Val substitutions significantly reduced the integrin-binding affinity and decreased HT1080 cell adhesion, with the effects stronger than Gly→Ala substitutions. Compared with Gly→Ala substitutions, substitution of Gly with the larger residue Val had enhanced negative effects on the structure and function of recombinant collagen. These findings provide new insights into the molecular mechanisms of osteogenesis imperfecta and offer theoretical references and experimental foundations for the design of collagen sequences and the development of collagen-based biomaterials.

摘要

胶原蛋白是动物体内各种组织和功能的重要基质蛋白,在生物材料中有着广泛应用。在Ⅰ型胶原蛋白中,三螺旋结构的Gly-Xaa-Yaa三联体中甘氨酸(Gly)的错义突变是成骨不全症(OI)的主要病因。临床表现呈现出显著的异质性,涵盖从轻度骨骼脆弱(Ⅰ型)到严重肢体畸形(Ⅲ型)以及围产期致死形式(Ⅱ型)的广泛疾病谱。本研究以重组胶原蛋白为模型,进一步阐明整合素结合序列GFPGER N端的Gly→Ala/Val突变是否会影响胶原蛋白的结构和功能,并探究错义突变影响胶原蛋白生物学功能的潜在机制。通过在GFPGER序列N端的七个Gly位置引入Ala和Val替代物,我们系统评估了这些氨基酸替换对重组胶原蛋白三螺旋结构、热稳定性、整合素结合能力和细胞黏附的影响。所有构建体均形成了稳定的三螺旋结构,但热稳定性略有受损。Gly→Val替换增加了重组胶原蛋白对胰蛋白酶的敏感性,这表明三螺旋结构存在局部构象扰动。此外,Gly→Val替换显著降低了整合素结合亲和力并减少了HT1080细胞黏附,其影响比Gly→Ala替换更强。与Gly→Ala替换相比,并将Gly替换为更大的残基Val对重组胶原蛋白的结构和功能具有更强的负面影响。这些发现为成骨不全症的分子机制提供了新见解,并为胶原蛋白序列设计和基于胶原蛋白的生物材料开发提供了理论参考和实验基础。

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