Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Hum Mol Genet. 2009 Dec 1;18(23):4546-51. doi: 10.1093/hmg/ddp416. Epub 2009 Sep 4.
X-linked dyskeratosis congenita (DC) is a rare bone marrow failure syndrome caused by mostly missense mutations in the pseudouridine synthase NAP57 (dyskerin/Cbf5). As part of H/ACA ribonucleoproteins (RNPs), NAP57 is important for the biogenesis of ribosomes, spliceosomal small nuclear RNPs, microRNAs and the telomerase RNP. DC mutations concentrate in the N- and C-termini of NAP57 but not in its central catalytic domain raising questions as to their impact. We demonstrate that the N- and C-termini together form the binding surface for the H/ACA RNP assembly factor SHQ1 and that DC mutations modulate the interaction between the two proteins. Pinpointing impaired interaction between NAP57 and SHQ1 as a potential molecular basis for X-linked DC has implications for therapeutic approaches, e.g. by targeting the NAP57-SHQ1 interface with small molecules.
X 连锁先天性角化不良（DC）是一种罕见的骨髓衰竭综合征，主要由假尿嘧啶合酶 NAP57（核仁素/Cbf5）的错义突变引起。作为 H/ACA 核糖核蛋白（RNP）的一部分，NAP57 对于核糖体、剪接体小核 RNP、microRNAs 和端粒酶 RNP 的生物发生至关重要。DC 突变集中在 NAP57 的 N-和 C-末端，但不在其中心催化结构域，这引发了关于其影响的问题。我们证明，NAP57 的 N-和 C-末端共同形成了与 H/ACA RNP 组装因子 SHQ1 的结合表面，并且 DC 突变调节了这两种蛋白之间的相互作用。将 NAP57 和 SHQ1 之间的相互作用受损确定为 X 连锁 DC 的潜在分子基础，这对治疗方法具有重要意义，例如通过用小分子靶向 NAP57-SHQ1 界面。
