Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains.
Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains.
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DOI：
10.1016/j.celrep.2016.01.079
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发表时间：
2016-03-22
期刊：
影响因子：
8.8
通讯作者：
Walters KJ
中科院分区：
文献类型：
--
作者：
He F;Wollscheid HP;Nowicka U;Biancospino M;Valentini E;Ehlinger A;Acconcia F;Magistrati E;Polo S;Walters KJ
肌球蛋白VI在早期内吞作用和自噬体成熟过程中对货物运输和分类至关重要，其异常与癌症、神经变性、耳聋和肥厚性心肌病有关。本文中，我们在myosin VI中发现了一个结构域MyUb （myosin VI泛素结合域），它与泛素链结合，特别是通过K63、K11和K29连接的泛素链。我们求解了MyUb的溶液结构，以及MyUb:K63-linked diubiquitin的溶液结构。MyUb折叠成一个紧凑的螺旋状基序，坐落在k63连接的二泛素的泛素之间，与每个泛素的不同表面相互作用。MyUb的c端螺旋（Helix2）上有9个氨基酸的延伸，这是肌球蛋白VI与内吞和自噬接头相互作用所必需的。结构导向突变揭示了MyUb的功能是优神经蛋白相互作用所必需的。此外，我们还发现一个异构体特异性螺旋限制了MyUb与泛素链的结合。这项工作为肌球蛋白VI与泛素化货物和功能适配器的相互作用提供了基本的见解。
Myosin VI is critical for cargo trafficking and sorting during early endocytosis and autophagosome maturation, with abnormalities linked to cancers, neurodegeneration, deafness, and hypertropic cardiomyopathy. Herein, we identify a structured domain in myosin VI, MyUb (Myosin VI Ubiquitin-binding domain), that binds to ubiquitin chains, especially those linked via K63, K11, and K29. We solve the solution structure of MyUb, and of MyUb:K63-linked diubiquitin. MyUb folds as a compact, helix-turn-helix-like motif and nestles between the ubiquitins of K63-linked diubiquitin, interacting with distinct surfaces of each. A nine amino acid extension at the C-terminal helix (Helix2) of MyUb is required for myosin VI interaction with endocytic and autophagic adaptors. Structure-guided mutations revealed that a functional MyUb is necessary for optineurin interaction. In addition, we found that an isoform-specific helix restricts MyUb binding to ubiquitin chains. This work provides fundamental insights into myosin VI interaction with ubiquitinated cargo and functional adaptors.