Sequence environment of mutation affects stability and folding in collagen model peptides of osteogenesis imperfecta.
Sequence environment of mutation affects stability and folding in collagen model peptides of osteogenesis imperfecta.
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DOI：
10.1002/bip.21432
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发表时间：
2011
期刊：
影响因子：
2.9
通讯作者：
Brodsky, Barbara
中科院分区：
文献类型：
--
作者：
Bryan, Michael A.;Cheng, Haiming;Brodsky, Barbara
成骨不全(OI)是一种以骨骼脆弱为特征的疾病，通常是I型胶原错义突变的结果，I型胶原错义突变使重复的(Gly-Xaaa-Yaa)n序列中的一个甘氨酸变成更大的氨基酸。使用两组三螺旋多肽考察了局部环境的影响和取代甘氨酸残基的同一性。将高度稳定的(Pro-Hyp-Gly)10系统中的Gly突变与T1-865肽中的突变进行比较，T1-865肽的突变位于较不稳定的天然胶原序列中。丙氨酸、丝氨酸或精氨酸取代甘氨酸残基会导致两种多肽系统中显著的三螺旋失稳。正如预期的那样，由于甘氨酸到丙氨酸或甘氨酸到丝氨酸的变化而导致的稳定性损失(ΔTM)在更刚性(Pro-Hyp-Gly)的10肽中比在T1-865组中更大。但(Pro-Hyp-Gly)10突变多肽的最终Tm值高于相应的T1-865突变多肽，这可能是更具生物学意义的参数。在这两种环境中，Gly到Arg的替代阻止了完全折叠的三螺旋结构的形成。用差示扫描量热法对折叠进行监测发现，T1-865肽中存在较低的稳定性物种和完全折叠的三螺旋分子，这些三螺旋分子被甘氨酸取代为丙氨酸或丝氨酸，并且这种较低的稳定性物种随时间消失。T1-865肽难以通过突变位点繁殖可能与OI胶原蛋白的延迟折叠有关，并表明折叠机制依赖于局部序列环境。
Osteogenesis Imperfecta (OI), a disorder characterized by fragile bones, is often a consequence of missense mutations in type I collagen which change one Gly in the repeating (Gly-Xaaa-Yaa)n sequence to a larger amino acid. The impact of local environment and the identity of the residue replacing Gly was investigated using two sets of triple-helical peptides. Gly mutations in the highly stable (Pro-Hyp-Gly)10 system are compared with mutations in T1-865 peptides where the mutation is located within a less stable natural collagen sequence. Replacement of a Gly residue by Ala, Ser, or Arg leads to significant triple-helical destabilization in both peptide systems. The loss of stability (ΔTm) due to a Gly to Ala or Gly to Ser change was greater in the more rigid (Pro-Hyp-Gly)10 peptides than in the T1-865 set, as expected. But the final Tm values, which may be the more biologically meaningful parameters, were higher for the (Pro-Hyp-Gly)10 mutation peptides than for the corresponding T1-865 mutation peptides. In both peptide environments, a Gly to Arg replacement prevented the formation of a fully folded triple-helix. Monitoring of folding by differential scanning calorimetry showed a lower stability species as well as the fully folded triple-helical molecules for T1-865 peptides with Gly to Ala or Ser replacements, and this lower stability species disappears as a function of time. The difficulty in propagation through a mutation site in T1-865 peptides may relate to the delayed folding seen in OI collagens, and indicates a dependence of folding mechanism on the local sequence environment.
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影响因子：
5.6
作者：
RAGHUNATH, M;BRUCKNER, P;STEINMANN, B
通讯作者：
STEINMANN, B
影响因子：
56.9
作者：
BELLA, J;EATON, M;BERMAN, HM
通讯作者：
BERMAN, HM
影响因子：
8
作者：
Persikov, AV;Xu, YJ;Brodsky, B
通讯作者：
Brodsky, B
DOI：
10.1002/ajmg.1320450204
发表时间：
1993-01-15
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
BACHINGER, HP;MORRIS, NP;DAVIS, JM
通讯作者：
DAVIS, JM
影响因子：
2.9
作者：
Liu, XY;Kim, S;Baum, J
通讯作者：
Baum, J