ESCRT-III recognition by VPS4 ATPases
ESCRT-III recognition by VPS4 ATPases
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DOI：
10.1038/nature06172
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发表时间：
2007-10-11
期刊：
影响因子：
64.8
通讯作者：
Sundquist, Wesley I.
中科院分区：
文献类型：
--
作者：
Stuchell-Brereton, Melissa D.;Skalicky, Jack J.;Sundquist, Wesley I.
ESCRT（转运所需的内体分选复合体）途径是几个重要生物过程中终末膜裂变事件所必需的，包括内体腔内囊泡形成 (1,2)、HIV 出芽 (3) 和胞质分裂 (4)。 VPS4 ATP 酶通过识别膜相关的 ESCRT-III 组装并催化其分解 (5-7)（可能与膜裂变结合），在此通路中发挥关键功能。在这里，我们展示了人 VPS4A 和 VPS4B 的微管相互作用和转运 (MIT) 结构域结合位于 ESCRT-III 蛋白 CHMP1-3 类羧基末端的保守序列基序。 VPS4A MIT-CHMP1A 和 VPS4B MIT-CHMP2B 复合物的结构表明，C 端 CHMP 基序形成两亲性螺旋，该螺旋结合在 VPS4 MIT 结构域的四三肽样重复 (TPR) 的最后两个螺旋之间的凹槽中，但方向与典型的 TPR 相互作用相反。 MIT 结构域中的不同口袋结合 CHMP 基序的三个保守亮氨酸残基，抑制这些相互作用的突变会阻止 VPS4 募集、损害内体蛋白分选并缓解显性失活 VPS4 对 HIV 出芽的抑制。因此，我们的研究揭示了 VPS4 ATP 酶如何识别其 CHMP 底物，以促进病毒、内体囊泡和子细胞释放所需的膜裂变事件。
The ESCRT (endosomal sorting complex required for transport) pathway is required for terminal membrane fission events in several important biological processes, including endosomal intraluminal vesicle formation(1,2), HIV budding(3) and cytokinesis(4). VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly(5-7), possibly in conjunction with membrane fission. Here we show that the microtubule interacting and transport (MIT) domains of human VPS4A and VPS4B bind conserved sequence motifs located at the carboxy termini of the CHMP1-3 class of ESCRT-III proteins. Structures of VPS4A MIT-CHMP1A and VPS4B MIT-CHMP2B complexes reveal that the C-terminal CHMP motif forms an amphipathic helix that binds in a groove between the last two helices of the tetratricopeptide-like repeat (TPR) of the VPS4 MIT domain, but in the opposite orientation to that of a canonical TPR interaction. Distinct pockets in the MIT domain bind three conserved leucine residues of the CHMP motif, and mutations that inhibit these interactions block VPS4 recruitment, impair endosomal protein sorting and relieve dominant-negative VPS4 inhibition of HIV budding. Thus, our studies reveal how the VPS4 ATPases recognize their CHMP substrates to facilitate the membrane fission events required for the release of viruses, endosomal vesicles and daughter cells.