Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex
Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex
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对 KANK1·KIF21A 复合物关键特征的结构分析可深入了解微管和细胞皮层之间的相互作用
DOI：
10.1074/jbc.m117.816017
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Weng Z;Shang Y;Yao D;Zhu J;Zhang R
动态微管和细胞皮层之间的相互作用在细胞分裂、极性和迁移中起着重要作用。连接微管正端与细胞皮质的关键接头是KANK N-末端基序和锚蛋白重复结构域1（KANK 1）/驱动蛋白家族成员21 A（KIF 21 A）复合物。这两种蛋白质的遗传缺陷与各种癌症和发育性疾病有关，例如先天性眼外肌纤维化1型。然而，KANK 1/KIF 21 A相互作用的分子机制和保守锚蛋白（ANK）重复序列在这种相互作用中的作用仍不清楚。在这项研究中，我们提出了KANK 1·KIF 21 A复合物的晶体结构在2.1纳米分辨率。该结构与生物化学研究一起揭示了KANK 1的ANK重复序列之前的五螺旋帽状结构域与其ANK重复序列形成了结构和功能超模块，其与位于KIF 21 A中间的进化上保守的肽结合。我们还发现，癌症患者中存在的几个错义突变位于KANK 1·KIF 21 A复合物的界面，并使其形成不稳定。总之，我们的研究阐明了KANK 1/KIF 21 A相互作用的分子基础，也为KANK 1和KIF 21 A突变引起的疾病提供了可能的机制解释。
The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle–capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.
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DOI：
10.1107/s0907444910045749
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Winn MD;Ballard CC;Cowtan KD;Dodson EJ;Emsley P;Evans PR;Keegan RM;Krissinel EB;Leslie AG;McCoy A;McNicholas SJ;Murshudov GN;Pannu NS;Potterton EA;Powell HR;Read RJ;Vagin A;Wilson KS
通讯作者：
Wilson KS
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1083/jcb.200805147
发表时间：
2009-01-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Roy BC;Kakinuma N;Kiyama R
通讯作者：
Kiyama R
影响因子：
9.2
作者：
Drabek, Ksenija;van Ham, Marco;Galjart, Niels
通讯作者：
Galjart, Niels