Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
PLoS One. 2020 Feb 19;15(2):e0229254. doi: 10.1371/journal.pone.0229254. eCollection 2020.
Activins are members of the transforming growth factor-β (TGF-β) superfamily of signaling proteins and were originally identified as components of follicular fluid. The proteins are now known to play critical roles in numerous normal and pathological processes and conditions, but less is clear about the relationships between their gene organization and protein variant expression and structure. The four human and mouse activin (Act) genes, termed INHβA, INHβB, INHβC and INHβE, differ in exon numbers. Human INHβA is the most complex with 7 exons and elicits production of three Act A variants (Act A X1, X2 and X3) differing in their pro-region, as we showed previously. Here we further analyzed the mouse INHβA gene and found that its 4 exons encode for a single open reading frame (mouse Act A), corresponding to the shortest human Act A X3 variant. Activins are synthesized and secreted as large complexes made of a long pro-region and a short mature C- terminal ligand and are known to interact with the heparan sulfate (HS) chains of cell surface and matrix proteoglycans. Human Act A X1 and X2 variants do have a HS-binding domain (HBD) with Cardin/Weintraub traits in their pro-region, while the X3 variant does not as shown previously. We found that the mouse Act A lacks a HBD as well. However, we identified a typical HBD in the pro-region of both mouse and human Act B, and synthetic peptides containing that domain interacted with immobilized HS and cell surface with nanomolar affinity. In sum, human and mouse Act A genes elicit expression of different variant sets, while there is concordance in Act B protein expression, reflecting possible evolutionary diversity in function of, and responses to, these signaling proteins in the two species.
激活素是转化生长因子-β（TGF-β）信号蛋白超家族的成员，最初被鉴定为卵泡液的组成部分。现在已知这些蛋白在许多正常和病理过程和状态中发挥关键作用，但它们的基因组织与蛋白变异表达和结构之间的关系还不太清楚。四种人类和小鼠激活素（Act）基因，称为 INHβA、INHβB、INHβC 和 INHβE，在exon 数量上存在差异。人类 INHβA 最为复杂，有 7 个 exon，可产生三种 Act A 变异体（Act A X1、X2 和 X3），它们在其前导区有所不同，正如我们之前所展示的。在这里，我们进一步分析了小鼠 INHβA 基因，发现其 4 个 exon 编码一个单一的开放阅读框（小鼠 Act A），对应于最短的人类 Act A X3 变异体。激活素作为由长前导区和短成熟 C 端配体组成的大型复合物被合成和分泌，并已知与细胞表面和基质蛋白聚糖的肝素硫酸（HS）链相互作用。如前所述，人类 Act A X1 和 X2 变异体在前导区确实具有 HS 结合域（HBD）和 Cardin/Weintraub 特征，但 X3 变异体没有。我们发现小鼠 Act A 也缺乏 HBD。然而，我们在小鼠和人类 Act B 的前导区中都鉴定出了一个典型的 HBD，并且含有该结构域的合成肽与固定化 HS 和细胞表面以纳摩尔亲和力相互作用。总之，人类和小鼠 Act A 基因引发不同变异体的表达，而 Act B 蛋白的表达则存在一致性，反映了这两种物种中这些信号蛋白在功能和对其反应方面可能存在进化多样性。
