The structure of human coagulation factor XIII (FXIII), a heterotetrameric plasma protransglutaminase that covalently cross-links preformed fibrin polymers, remains elusive until today. The heterotetrameric complex is composed of 2 catalytic FXIII-A and 2 protective FXIII-B subunits. Structural etiology underlying FXIII deficiency has so far been derived from crystallographic structures, all of which are currently available for the FXIII-A2 homodimer only. Here, we present the cryogenic electron microscopy structure of a native, human plasma–derived FXIII-A2B2 complex at 2.4 Å resolution. The structure provides detailed information on FXIII subunit interacting interfaces as the 2 subunits interact strongly in plasma. The native FXIII-A2B2 complex reveals a pseudosymmetric heterotetramer of 2 FXIII-B monomers intercalating with a symmetric FXIII-A2 dimer forming a “crown”-like assembly. The symmetry axes of the A2 and B2 homodimers are twisted relative to each other such that Sushi domain 1 interacts with the catalytic core of the A subunit, and Sushi domain 2 with the symmetry related A′ subunit, and vice versa. We also report 4 novel mutations in the F13A1 gene encoding the FXIII-A subunit from a cohort of patients with severe FXIII deficiency. Our structure reveals the etiological basis of homozygous and heterozygous pathogenic mutations and explains the conditional dominant negative effects of heterozygous mutations. This atomistic description of complex interfaces is consistent with previous biochemical data and shows a congruence between the structural biochemistry of the FXIII complex and the clinical features of FXIII deficiency.

中文翻译：

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人类天然血浆凝血因子 XIII 复合物的冷冻电镜结构


人凝血因子 XIII （FXIII） 的结构是一种异四聚体血浆转谷氨酰胺酶原，可共价交联预先形成的纤维蛋白聚合物，直到今天仍然难以捉摸。异四聚体复合物由 2 个催化 FXIII-A 和 2 个保护性 FXIII-B 亚基组成。迄今为止，FXIII 缺陷的结构病因来自晶体学结构，所有这些结构目前仅适用于 FXIII-A2 同型二聚体。在这里，我们展示了 2.4 Å 分辨率的天然人血浆衍生 FXIII-A2B2 复合物的低温电子显微镜结构。该结构提供了有关 FXIII 亚基相互作用界面的详细信息，因为 2 个亚基在血浆中强烈相互作用。天然 FXIII-A2B2 复合物揭示了 2 个 FXIII-B 单体的伪对称异四聚体与对称 FXIII-A2 二聚体嵌入，形成“冠状”组装体。A2 和 B2 同源二聚体的对称轴相对于彼此扭曲，使得 Sushi 结构域 1 与 A 亚基的催化核心相互作用，而 Sushi 结构域 2 与对称性相关的 A′ 亚基相互作用，反之亦然。我们还报告了来自一组严重 FXIII 缺陷患者编码 FXIII-A 亚基的 F13A1 基因的 4 个新突变。我们的结构揭示了纯合子和杂合子致病突变的病因基础，并解释了杂合突变的条件性显性负面影响。这种复杂界面的原子描述与以前的生化数据一致，并表明 FXIII 复合物的结构生化与 FXIII 缺陷的临床特征之间存在一致性。