Chain alignment of collagen I deciphered using computationally designed heterotrimers
Chain alignment of collagen I deciphered using computationally designed heterotrimers
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DOI：
10.1038/s41589-019-0435-y
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发表时间：
2020-01-06
影响因子：
14.8
通讯作者：
Farndale, Richard W.
中科院分区：
文献类型：
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作者：
Jalan, Abhishek A.;Sammon, Douglas;Farndale, Richard W.
胶原蛋白家族中最丰富的成员胶原蛋白I（也称为I型胶原蛋白; COL 1）由一个独特的（链B）和两个相似的（链A）多肽组成，所述多肽以一个氨基酸偏移自组装成异源三聚体三螺旋。考虑到偏移，链B可以占据三螺旋的前导（BAA）、中间（阿坝）或拖尾（AAB）位置，产生具有不同蛋白质识别特性的三种异构生物大分子。尽管经过了五十年的深入研究，但对于Col 1中链B的位置尚未达成共识。在这里，三个三螺旋异源三聚体，每个包含一个假定的血管性血友病因子（VWF）和盘状结构域受体（DDR）的识别序列，从COL 1的设计与链B置换在所有三个位置。AAB表现出对VWF和DDR的强烈偏好，并且还诱导更高水平的细胞DDR磷酸化。因此，我们解决了这个长期存在的谜团，并表明，COL 1采用AAB register.Designed异源三聚体的胶原蛋白I，锁定在三个可能的链寄存器，使结构和功能表征的每个排列，导致识别的AAB异源三聚体作为最活跃的，因此可能发生生物学。
The most abundant member of the collagen protein family, collagen I (also known as type I collagen; COL1), is composed of one unique (chain B) and two similar (chain A) polypeptides that self-assemble with one amino acid offset into a heterotrimeric triple helix. Given the offset, chain B can occupy either the leading (BAA), middle (ABA) or trailing (AAB) position of the triple helix, yielding three isomeric biomacromolecules with different protein recognition properties. Despite five decades of intensive research, there is no consensus on the position of chain B in COL1. Here, three triple-helical heterotrimers that each contain a putative von Willebrand factor (VWF) and discoidin domain receptor (DDR) recognition sequence from COL1 were designed with chain B permutated in all three positions. AAB demonstrated a strong preference for both VWF and DDR, and also induced higher levels of cellular DDR phosphorylation. Thus, we resolve this long-standing mystery and show that COL1 adopts an AAB register.Designed heterotrimers of collagen I, locked in three possible chain registers, enable structural and functional characterization of each permutation, leading to identification of the AAB heterotrimer as the most active and therefore likely to occur biologically.