Cellular functions of γ-secretase-related proteins
Cellular functions of γ-secretase-related proteins
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DOI：
10.1159/000095268
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发表时间：
2006-01-01
影响因子：
3
通讯作者：
Haass, Christian
中科院分区：
文献类型：
--
作者：
Haffner, Christof;Haass, Christian
淀粉样蛋白- β颗粒（A β）是由γ -分泌酶产生的，γ -分泌酶是一种具有异常天冬氨酸蛋白酶活性的膜蛋白复合物，由早老素、nicastrin、APH-1和PEN-2组成。早老素被认为是该复合物的催化亚基，因为它代表了膜内切割gxgd型天冬氨酸蛋白酶新家族的原型。最近，该家族的5个新成员和一种nicastrin样蛋白被鉴定出来。虽然gxgd型蛋白中的一种被证明与信号肽酶（SPP）相同，但其他被称为SPP样蛋白（SPPLs）的功能尚不清楚。因此，我们分析了SPPL2b和SPPL3，并证明它们定位于不同的亚细胞区室，表明它们具有非冗余功能。在斑马鱼胚胎的敲低研究中获得的不同表型支持了这一点。此外，这些表型可以通过推测的活性位点突变体的异位表达来表型，这为SPPL2b和SPPL3具有蛋白水解功能提供了强有力的证据。我们还鉴定并表征了nicastrin样蛋白nicalin，它与130 kda蛋白NOMO（节点调节剂）一起形成不同于γ -分泌酶的膜蛋白复合物。我们发现，在斑马鱼胚胎发生过程中，该复合体参与了轴向中胚层的形成，这是一个由节点信号通路控制的过程。版权所有(c) 2006 S. Karger AG，巴塞尔。
Amyloid-beta pepticle (A beta) is generated by gamma-secretase, a membrane protein complex with an unusual aspartyl protease activity consisting of the four components presenilin, nicastrin, APH-1 and PEN-2. Presenilin is considered the catalytic subunit of this complex since it represents the prototype of the new family of intramembrane-cleaving GxGD-type aspartyl proteases. Recently, five novel members of this family and a nicastrin-like protein were identified. Whereas one of the GxGD-type proteins was shown to be identical with signal pepticle peptidase (SPP), the function of the others, now called SPP-like proteins (SPPLs), is not known. We therefore analyzed SPPL2b and SPPL3 and demonstrated that they localize to different subcellular compartments suggesting nonredundant functions. This was supported by different phenotypes obtained in knockdown studies in zebrafish embryos. In addition, these phenotypes could be phenocopied by ectopic expression of putative active site mutants, providing strong evidence for a proteolytic function of SPPL2b and SPPL3. We also identified and characterized the nicastrin-like protein nicalin which, together with the 130-kDa protein NOMO (Nodal modulator), forms a membrane protein complex different from gamma-secretase. We found that during zebrafish embryogenesis this complex is involved in the patterning of the axial mesendoderm, a process controlled by the Nodal signaling pathway. Copyright (c) 2006 S. Karger AG, Basel.