Oligomer-to-monomer transition underlies the chaperone function of AAGAB in AP1/AP2 assembly.
Oligomer-to-monomer transition underlies the chaperone function of AAGAB in AP1/AP2 assembly.
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DOI：
10.1073/pnas.2205199120
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发表时间：
2023-01-10
影响因子：
11.1
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中科院分区：
文献类型：
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AAGAB是控制接头复合物1和2（AP 1和AP 2）的组装的组装分子伴侣。AAGAB基因突变导致皮肤病点状掌跖角化病1型（PPKP 1）。我们发现，C-末端结构域（CTD），往往在PPKP 1患者的突变蛋白中缺失，通过形成反平行二聚体介导AAGAB同源二聚化。有趣的是，CTD还以1：1的化学计量结合并稳定AP 1复合物中的γ亚基或AP 2复合物中的α亚基。我们的研究结果证明了AAGAB的双重作用，并为致病AAGAB突变提供了分子解释。寡聚化状态转换机制也可能是其他组装分子伴侣功能的基础。蛋白质复合物的组装通过组装分子伴侣促进。α和γ适配素结合蛋白（AAGAB）是一种分子伴侣，控制异源四聚体适配体复合物1和2（AP 1和AP 2）的组装，参与网格蛋白介导的膜运输。在这里，我们发现在AP 1/2结合之前，AAGAB以同源二聚体形式存在。AAGAB二聚化由其C-末端结构域（CTD）介导，其对于AAGAB稳定性至关重要，并且在患有皮肤病1型点状掌跖角化病（PPKP 1）的患者中发现的突变蛋白中缺失。我们解决了二聚介导的CTD的晶体结构，揭示了弯曲螺旋的反平行二聚体。有趣的是，AAGAB使用相同的CTD来识别和稳定AP 1复合物中的γ亚基和AP 2复合物中的α亚基，形成仅含有一个AAGAB拷贝的二元复合物。这些发现证明了CTD在稳定静息AAGAB和结合底物方面的双重作用，为致病AAGAB突变提供了分子解释。寡聚化状态转换机制也可能是其他组装分子伴侣功能的基础。
AAGAB is an assembly chaperone governing the assembly of the adaptor complexes 1 and 2(AP1 and AP2). Mutations on the AAGAB gene cause the skin disease punctate palmoplantar keratoderma type 1 (PPKP1). We found that the C-terminal domain (CTD), often missing in the mutant protein in PPKP1 patients, mediates AAGAB homodimerization by forming an antiparallel dimer. Interestingly, CTD also binds and stabilizes the γ subunit in the AP1 complex or the α subunit in the AP2 complex in a 1:1 stoichiometry. Our findings demonstrate a dual role of AAGAB and provide a molecular explanation for disease-causing AAGAB mutations. The oligomerization state transition mechanism may also underlie the functions of other assembly chaperones. Assembly of protein complexes is facilitated by assembly chaperones. Alpha and gamma adaptin-binding protein (AAGAB) is a chaperone governing the assembly of the heterotetrameric adaptor complexes 1 and 2 (AP1 and AP2) involved in clathrin-mediated membrane trafficking. Here, we found that before AP1/2 binding, AAGAB exists as a homodimer. AAGAB dimerization is mediated by its C-terminal domain (CTD), which is critical for AAGAB stability and is missing in mutant proteins found in patients with the skin disease punctate palmoplantar keratoderma type 1 (PPKP1). We solved the crystal structure of the dimerization-mediating CTD, revealing an antiparallel dimer of bent helices. Interestingly, AAGAB uses the same CTD to recognize and stabilize the γ subunit in the AP1 complex and the α subunit in the AP2 complex, forming binary complexes containing only one copy of AAGAB. These findings demonstrate a dual role of CTD in stabilizing resting AAGAB and binding to substrates, providing a molecular explanation for disease-causing AAGAB mutations. The oligomerization state transition mechanism may also underlie the functions of other assembly chaperones.
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影响因子：
64.5
作者：
Ren X;Farías GG;Canagarajah BJ;Bonifacino JS;Hurley JH
通讯作者：
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