Nuclear magnetic resonance shows asymmetric loss of triple helix in peptides modeling a collagen mutation in brittle bone disease
Nuclear magnetic resonance shows asymmetric loss of triple helix in peptides modeling a collagen mutation in brittle bone disease
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DOI：
10.1021/bi981147u
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发表时间：
1998-11-03
期刊：
影响因子：
2.9
通讯作者：
Baum, J
中科院分区：
文献类型：
--
作者：
Liu, XY;Kim, S;Baum, J
为了研究一种人类折叠疾病，对类胶原肽进行了核磁共振研究，以确定在成骨不全(OI)患者中发现的单一氨基酸变化的结构后果，OI是一种以骨骼脆弱为特征的疾病。在一例非致死性OI中发现的一种多肽包括正常的胶原蛋白序列，而第二种多肽包括Gly-->；Ser取代。残基特定的内部动力学和构象研究表明，正常的胶原样序列形成一个沿其整个长度刚性的三螺旋。Gly-->；Ser取代的引入诱导了均匀三螺旋的不对称破坏。当C端保留三螺旋时，Ser取代位点和N端残基表现出随机链的移动性。这种平衡状态表明，甘氨酸取代可以终止三螺旋的C到N传播，并表明需要重成核才能继续折叠。有缺陷的折叠与脆性骨病有关，这些结果开始描述OI胶原蛋白的折叠过程。OI胶原蛋白的研究也可能提供有关其他人类疾病中有缺陷的蛋白质折叠、组装和聚集的见解。
TO investigate a human folding disease, NMR studies were carried out on collagen-like peptides to define the structural consequences of a single amino acid change found in patients with osteogenesis imperfecta (OI), a disease characterized by fragile bones. One peptide included a normal collagen sequence, while a second peptide included a Gly --> Ser substitution as found in a nonlethal case of OI. Residue specific internal dynamics and conformational studies indicate that the normal collagen-like sequence forms a triple helix which is rigid along its entire length. The introduction of a Gly --> Ser substitution induces an asymmetric disruption of the uniform triple helix. While the C-terminal end of the peptide retains the triple helix, the Ser substitution site and residues N-terminal to it exhibit the mobility of a random chain. This equilibrium state indicates that a Gly substitution can terminate the C to N propagation of the triple helix and suggests that renucleation is required for folding to continue. Defective folding has been implicated in brittle bone disease, and these results begin to characterize the folding process in OI collagens. OI collagen studies may also provide insights about defective protein folding, assembly, and aggregation in other human diseases.