Porter J A, von Kessler D P, Ekker S C, Young K E, Lee J J, Moses K, Beachy P A
Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Nature. 1995 Mar 23;374(6520):363-6. doi: 10.1038/374363a0.
The secreted protein products of the hedgehog (hh) gene family are associated with local and long-range signalling activities that are responsible for developmental patterning in multiple systems, including Drosophila embryonic and larval tissues and vertebrate neural tube, limbs and somites. In a process that is critical for full biological activity, the hedgehog protein (Hh) undergoes autoproteolysis to generate two biochemically distinct products, an 18K amino-terminal fragment, N, and a 25K carboxy-terminal fragment, C (ref. 16); mutations that block autoproteolysis impair Hh function. We have identified the site of autoproteolytic cleavage and find that it is broadly conserved throughout the hedgehog family. Knowing the site of cleavage, we were able to test the function of the N and C cleavage products in Drosophila assays. We show here that the N product is the active species in both local and long-range signalling. Consistent with this, all twelve mapped hedgehog mutations either affected the structure of the N product directly or otherwise blocked the release of N from the Hh precursor as a result of deletion or alteration of sequences in the C domain.
刺猬基因（hh）家族的分泌蛋白产物与局部和远距离信号传导活动相关，这些活动负责多个系统的发育模式形成，包括果蝇胚胎和幼虫组织以及脊椎动物的神经管、肢体和体节。在一个对完整生物活性至关重要的过程中，刺猬蛋白（Hh）进行自蛋白水解以产生两种生化性质不同的产物，一个18K的氨基末端片段N和一个25K的羧基末端片段C（参考文献16）；阻断自蛋白水解的突变会损害Hh功能。我们已经确定了自蛋白水解切割位点，并发现它在整个刺猬家族中广泛保守。知道了切割位点，我们能够在果蝇实验中测试N和C切割产物的功能。我们在此表明，N产物在局部和远距离信号传导中都是活性物种。与此一致的是，所有十二个已定位的刺猬突变要么直接影响N产物的结构，要么由于C结构域中序列的缺失或改变而阻止N从Hh前体中释放。
