Kinked Collagen VI Tetramers and Reduced Microfibril Formation as a Result of Bethlem Myopathy and Introduced Triple Helical Glycine Mutations*
Kinked Collagen VI Tetramers and Reduced Microfibril Formation as a Result of Bethlem Myopathy and Introduced Triple Helical Glycine Mutations*
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贝特莱姆肌病和引入的三螺旋甘氨酸突变导致 VI 型胶原蛋白四聚体扭结和微原纤维形成减少*
DOI：
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发表时间：
2002
影响因子：
4.8
通讯作者：
J. Bateman
中科院分区：
文献类型：
--
作者：
S. Lamandé;M. Mörgelin;Carly Selan;G. J. Jöbsis;F. Baas;J. Bateman
编码胶原VI亚单位COL 6A 1、COL 6A 2和COL 6A 3的基因突变是显性遗传疾病Bethlem肌病的原因。甘氨酸突变中断的Gly-X-Y重复的氨基酸序列，形成特征性的胶原蛋白三螺旋已被定义在四个家庭，然而，这些突变对胶原蛋白VI的生物合成，组装和结构的影响尚未确定。在这项研究中，我们检查了Bethlem肌病α1（VI）和α2（VI）链中三螺旋甘氨酸突变的后果，以及工程α3（VI）三螺旋甘氨酸突变。尽管Bethlem肌病和朝向三螺旋N末端的引入突变对胶原VI细胞内单体、二聚体或四聚体组装或分泌没有可测量的影响，但朝向螺旋C末端的引入突变严重损害了突变α3（VI）链与α1（VI）和α2（VI）的结合。然而，三条链的结合没有完全被阻止，并且分泌了一些非二硫键键合的四聚体。通过负染色电子显微镜检查分泌的Bethlem肌病和工程化突变型胶原VI，发现了一个惊人的发现，即在所有细胞系中，显著比例的四聚体在超螺旋三螺旋区域中含有扭结。来自所有突变细胞系的胶原VI四聚体也显示出形成微原纤维的能力降低。这些结果提供了第一个证据的生物合成后果的胶原VI三螺旋甘氨酸突变，并表明Bethlem肌病的结果不仅从合成的减少量的结构正常的蛋白质，但也从存在的突变型胶原VI在细胞外基质。
Mutations in the genes that code for collagen VI subunits, COL6A1, COL6A2, andCOL6A3, are the cause of the dominantly inherited disorder, Bethlem myopathy. Glycine mutations that interrupt the Gly-X-Y repetitive amino acid sequence that forms the characteristic collagen triple helix have been defined in four families; however, the effects of these mutations on collagen VI biosynthesis, assembly, and structure have not been determined. In this study, we examined the consequences of Bethlem myopathy triple helical glycine mutations in the α1(VI) and α2(VI) chains, as well as engineered α3(VI) triple helical glycine mutations. Although the Bethlem myopathy and introduced mutations that are toward the N terminus of the triple helix did not measurably affect collagen VI intracellular monomer, dimer, or tetramer assembly, or secretion, the introduced mutation toward the C terminus of the helix severely impaired association of the mutant α3(VI) chain with α1(VI) and α2(VI). Association of the three chains was not completely prevented, however; and some non-disulfide bonded tetramers were secreted. Examination of the secreted Bethlem myopathy and engineered mutant collagen VI by negative staining electron microscopy revealed the striking finding that in all the cell lines a significant proportion of the tetramers contained a kink in the supercoiled triple helical region. Collagen VI tetramers from all of the mutant cell lines also showed a reduced ability to form microfibrils. These results provide the first evidence of the biosynthetic consequences of collagen VI triple helical glycine mutations and indicate that Bethlem myopathy results not only from the synthesis of reduced amounts of structurally normal protein but also from the presence of mutant collagen VI in the extracellular matrix.
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在患有致死性成骨不全的先证者中，用半胱氨酸取代 I 型原胶原原 α 1(I) 链中的甘氨酸-α 1-691 会破坏取代位点 C 端三螺旋的稳定性。
DOI：
10.1042/bj2790747
发表时间：
1991
期刊：
The Biochemical journal
影响因子：
--
作者：
Steinmann,B;Westerhausen,A;Constantinou,CD;Superti-Furga,A;Prockop,DJ
通讯作者：
Prockop,DJ
DOI：
10.1016/s0021-9258(18)37416-7
发表时间：
1988-12
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
B. Vogel;R. Doelz;K. Kadler;Y. Hojima;J. Engel;D. Prockop
通讯作者：
B. Vogel;R. Doelz;K. Kadler;Y. Hojima;J. Engel;D. Prockop
鸡胚血管中 III 型前胶原生物合成的链组装中间体。
DOI：
--
发表时间：
1981
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bächinger,HP;Fessler,LI;Timpl,R;Fessler,JH
通讯作者：
Fessler,JH
Bethlem 肌病基因座异质性以及与 2q37 连锁的证据。
影响因子：
3.5
作者：
Speer,MC;Tandan,R;Rao,PN;Fries,T;Stajich,JM;Bolhuis,PA;Jöbsis,GJ;Vance,JM;Viles,KD;Sheffield,K;James,C;Kahler,SG;Pettenati,M;Gilbert,JR;Denton,PH;Yamaoka,LH;Pericak-Vance,MA
通讯作者：
Pericak-Vance,MA
影响因子：
4.8
作者：
Lamandé, SR;Sigalas, E;Bateman, JR
通讯作者：
Bateman, JR