Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, IL 61801, USA.
J Cell Sci. 2011 Sep 15;124(Pt 18):3060-5. doi: 10.1242/jcs.086751. Epub 2011 Aug 24.
Fragile X mental retardation protein (FMRP) is required for normal cognition. FMRP has two autosomal paralogs, which although similar to FMRP, cannot compensate for the loss of FMRP expression in brain. The arginine- and glycine-rich region of FMRP (the RGG box) is unique; it is the high-affinity RNA-binding motif in FMRP and is encoded by exon 15. Alternative splicing occurs in the 5' end of exon 15, which is predicted to affect the structure of the distally encoded RGG box. Here, we provide evidence that isoform 3, which removes 25 amino acids from the 5' end of exon 15, has an altered conformation that reduces binding of a specific antibody and renders the RGG box unable to efficiently associate with polyribosomes. Isoform 3 is also compromised in its ability to form granules and to associate with a key messenger ribonucleoprotein Yb1 (also known as p50, NSEP1 and YBX1). Significantly, these functions are similarly compromised when the RGG box is absent from FMRP, suggesting an important regulatory role of the N-terminal region encoded by exon 15.
脆性 X 智力低下蛋白（FMRP）是正常认知所必需的。FMRP 有两个常染色体的同源物，虽然与 FMRP 相似，但不能弥补脑中 FMRP 表达的缺失。FMRP 的精氨酸和甘氨酸丰富区（RGG 盒）是独特的；它是 FMRP 中的高亲和力 RNA 结合基序，由外显子 15 编码。外显子 15 的 5'端发生选择性剪接，据预测这会影响远端编码的 RGG 盒的结构。在这里，我们提供的证据表明，从外显子 15 的 5'端去除 25 个氨基酸的 3 型异构体具有改变的构象，降低了与特定抗体的结合，并使 RGG 盒无法有效地与多核糖体结合。3 型异构体也无法形成颗粒，也无法与关键的信使核糖核蛋白 Yb1（也称为 p50、NSEP1 和 YBX1）结合。重要的是，当 FMRP 中不存在 RGG 盒时，这些功能也同样受到损害，这表明外显子 15 编码的 N 端区域具有重要的调节作用。
