Porter J A, Ekker S C, Park W J, von Kessler D P, Young K E, Chen C H, Ma Y, Woods A S, Cotter R J, Koonin E V, Beachy P A
Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
Cell. 1996 Jul 12;86(1):21-34. doi: 10.1016/s0092-8674(00)80074-4.
Autocatalytic processing mediated by the carboxyterminal domain of the hedgehog (hh) protein precursor (Hh) generates an amino-terminal product that accounts for all known signaling activity. The role of autoprocessing biogenesis of the hh signal has been unclear, since a truncated unprocessed protein lacking all carboxy-terminal domain sequences retains signaling activity. Here, we present evidence that the autoprocessing reaction proceeds via an internal thioester intermediate and results in a covalent modification that increases the hydrophobic character of the signaling domain and influences its spatial and subcellular distribution. We demonstrate that truncated unprocessed amino-terminal protein causes embryonic mispatterning, even when expression is localized to cells that normally express Hh, thus suggesting a role for autoprocessing in spatial regulation of hh signaling. This type of processing also appears to operate in the biogenesis of other novel secreted proteins.
由刺猬蛋白（hh）前体（Hh）的羧基末端结构域介导的自催化加工产生一种氨基末端产物，该产物具有所有已知的信号传导活性。hh信号的自加工生物合成作用一直不清楚，因为一种缺少所有羧基末端结构域序列的截短的未加工蛋白仍保留信号传导活性。在此，我们提供证据表明，自加工反应通过内部硫酯中间体进行，并导致一种共价修饰，这种修饰增加了信号结构域的疏水特性，并影响其空间和亚细胞分布。我们证明，即使截短的未加工氨基末端蛋白的表达定位于正常表达Hh的细胞，它也会导致胚胎模式异常，从而表明自加工在hh信号的空间调节中起作用。这种加工类型似乎也在其他新型分泌蛋白的生物合成中起作用。
