Protein L-isoaspartyl methyltransferase repairs abnormal aspartyl residues accumulated in vivo in type-I collagen and restores cell migration
Protein L-isoaspartyl methyltransferase repairs abnormal aspartyl residues accumulated in vivo in type-I collagen and restores cell migration
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DOI：
10.1016/j.yexcr.2003.10.003
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发表时间：
2004-02-01
影响因子：
3.7
通讯作者：
Desrosiers, RR
中科院分区：
文献类型：
--
作者：
Lanthier, J;Desrosiers, RR
在长寿命蛋白质的老化过程中，经常会出现异常的乙酰基残基形成，如L-异戊二酸酯，导致其结构和生物学功能的改变。在这项研究中，我们研究了在细胞外基质（ECM）蛋白，I型胶原蛋白和纤连蛋白，并在整合素和ECM结合基序在老化过程中，以及由此产生的影响细胞的生物学功能，如迁移和附着的乙酰基残基的改变。使用蛋白质L-异戊酰甲基转移酶（PIMT）来监测L-异戊酰残基的存在，我们显示了它们在大鼠I型胶原体内老化过程中的积累。纤连蛋白以及含有整联蛋白或ECM结合基序的肽如RGDSR、KDGEA和KCl的体外老化也导致L-异戊酰基残基的形成。虽然老年纤连蛋白不改变细胞粘附和迁移，I型胶原年龄20个月减少了65%的细胞运动，但不粘附，相比3个月的年龄I型胶原。最后，通过用重组PIMT（rPIMT）修复20个月大的I型胶原，细胞迁移恢复了72%。这些结果强烈表明，L-异戊酰基残基形成ECM蛋白，如I型胶原蛋白，可以发挥重要作用，减少细胞迁移和PIMT可以是一种治疗工具，以恢复正常的细胞迁移的病理条件下，细胞运动是至关重要的。(C)2003年爱思唯尔公司All rights reserved.
Abnormal aspartyl residue formation such as L-isoaspartates occurs frequently during aging in long-lived proteins, resulting in the alteration of their structures and biological functions. In this study, we investigated the alteration of aspartyl residues in extracellular matrix (ECM) proteins, type-I collagen and fibronectin, and in integrin- and ECM-binding motifs during aging, as well as the resulting effects on cell biological functions such as migration and attachment. Using protein L-isoaspartyl methyltransferase (PIMT) to monitor the presence of L-isoaspartyl residues, we showed their accumulation during in vivo aging in type-I collagen from rats. In vitro aging of fibronectin as well as of peptides containing an integrin- or ECM-binding motif such as RGDSR, KDGEA and KDDL also resulted in the formation Of L-isoaspartyl residues. While aged fibronectin does not alter cell adhesion and migration, type-I collagen aged 20 months reduced by 65% cell motility, but not adhesion, when compared to 3-month-aged type-I collagen. Finally, by repairing 20-month-old type-I collagen with recombinant PIMT (rPIMT), cell migration was recovered by 72%. These results strongly suggest that L-isoaspartyl residue formation in ECM proteins such as type-I collagen could play an important role in reducing cell migration and that PIMT could be a therapeutic tool to restore normal cell migration in pathological conditions where cell motility is crucial. (C) 2003 Elsevier Inc. All rights reserved.