Epstein J A, Glaser T, Cai J, Jepeal L, Walton D S, Maas R L
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Genes Dev. 1994 Sep 1;8(17):2022-34. doi: 10.1101/gad.8.17.2022.
Vertebrate Pax proteins share a conserved 128-amino-acid DNA-binding motif, the paired domain. The PAX6 gene, which is mutated in the murine Small eye and human aniridia developmental defects, also encodes a second protein with a 14-amino-acid insertion in the paired domain. This protein, which arises by alternative mRNA splicing, exhibits unique DNA-binding properties. Unlike other paired domains, which bind DNA predominantly by their amino termini, the extended Pax6 paired domain interacts with DNA exclusively through its carboxyl terminus. This property can be stimulated by deletion of 30 amino-terminal residues from the Pax6 or Pax2 paired domains. Thus, the insertion acts as a molecular toggle to unmask the DNA-binding potential of the carboxyl terminus. The functional nonequivalence of the two Pax6 proteins is underscored by a T-->C mutation at position -3 of the alternative splice acceptor site that changes the ratio of the two isoforms and causes a distinct human ocular syndrome.
脊椎动物的Pax蛋白共享一个保守的128个氨基酸的DNA结合基序,即配对结构域。PAX6基因在小鼠小眼症和人类无虹膜发育缺陷中发生突变,它还编码另一种在配对结构域中有14个氨基酸插入的蛋白质。这种通过可变mRNA剪接产生的蛋白质具有独特的DNA结合特性。与其他主要通过氨基末端结合DNA的配对结构域不同,扩展的Pax6配对结构域仅通过其羧基末端与DNA相互作用。从Pax6或Pax2配对结构域中删除30个氨基末端残基可增强这种特性。因此,该插入起到分子开关的作用,以揭示羧基末端的DNA结合潜力。可变剪接受体位点-3处的T→C突变改变了两种异构体的比例并导致一种独特的人类眼部综合征,这突出了两种Pax6蛋白的功能不等效性。