The interdomain flexible linker of the polypeptide GalNAc transferases dictates their long-range glycosylation preferences.
The interdomain flexible linker of the polypeptide GalNAc transferases dictates their long-range glycosylation preferences.
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DOI：
10.1038/s41467-017-02006-0
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发表时间：
2017-12-05
影响因子：
16.6
通讯作者：
Hurtado-Guerrero R
中科院分区：
文献类型：
--
作者：
de Las Rivas M;Lira-Navarrete E;Daniel EJP;Compañón I;Coelho H;Diniz A;Jiménez-Barbero J;Peregrina JM;Clausen H;Corzana F;Marcelo F;Jiménez-Osés G;Gerken TA;Hurtado-Guerrero R
GalNAc-转移酶(GalNAc-ts)是启动粘蛋白O-糖基化的多肽，由一个柔性连接子连接一个催化结构域和一个凝集素结构域。除了识别多肽序列外，GalNAc-ts还表现出独特的N端和/或C端糖基化(GalNAc-O-Ser/Thr)偏好，受凝集素结构域的调控。在这里，我们报道了关于GalNAc-T4的研究，揭示了其独特的N末端长程糖肽特异性的起源，这与GalNAc-T2相反。与单糖肽结合的GalNAc-T4结构表明，其凝集素结构域的GalNAc结合部位相对于同源的GalNAc-T2结构旋转，解释了它们不同的长程偏好。对几个GalNAc-T2柔性连接体结构的动力学和分子动力学模拟表明，远程先前的糖基化偏好发生了改变，证实了柔性连接体决定了凝集素结构域的旋转，从而调节了GalNAc-TS的长期偏好。这项工作首次为GalNAc-ts不同的远程先前糖基化偏好提供了结构基础。GalNAc转移酶(GalNAc-ts)的催化域通过一个柔性连接子连接到一个凝集素结构域。在这里，作者提出了一种GalNAc-T4的结构分析，它暗示连接区是凝集素结构域取向的调节器，这反过来又赋予底物特异性。
The polypeptide GalNAc-transferases (GalNAc-Ts), that initiate mucin-type O-glycosylation, consist of a catalytic and a lectin domain connected by a flexible linker. In addition to recognizing polypeptide sequence, the GalNAc-Ts exhibit unique long-range N- and/or C-terminal prior glycosylation (GalNAc-O-Ser/Thr) preferences modulated by the lectin domain. Here we report studies on GalNAc-T4 that reveal the origins of its unique N-terminal long-range glycopeptide specificity, which is the opposite of GalNAc-T2. The GalNAc-T4 structure bound to a monoglycopeptide shows that the GalNAc-binding site of its lectin domain is rotated relative to the homologous GalNAc-T2 structure, explaining their different long-range preferences. Kinetics and molecular dynamics simulations on several GalNAc-T2 flexible linker constructs show altered remote prior glycosylation preferences, confirming that the flexible linker dictates the rotation of the lectin domain, thus modulating the GalNAc-Ts' long-range preferences. This work for the first time provides the structural basis for the different remote prior glycosylation preferences of the GalNAc-Ts. GalNAc transferases’ (GalNAc-Ts) catalytic domains are connected to a lectin domain through a flexible linker. Here the authors present a structural analysis of GalNAc-T4 that implicates the linker region as modulator of the orientations of the lectin domain, which in turn imparts substrate specificity.
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影响因子：
16.6
作者：
Lira-Navarrete, Erandi;de las Rivas, Matilde;Companon, Ismael;Carmen Pallares, Maria;Kong, Yun;Iglesias-Fernandez, Javier;Bernardes, Goncalo J. L.;Peregrina, Jesus M.;Rovira, Carme;Bernado, Pau;Bruscolini, Pierpaolo;Clausen, Henrik;Lostao, Anabel;Corzana, Francisco;Hurtado-Guerrero, Ramon
通讯作者：
Hurtado-Guerrero, Ramon
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.7
作者：
Schjoldager, Katrine T.;Joshi, Hiren J.;Clausen, Henrik
通讯作者：
Clausen, Henrik
影响因子：
4.8
作者：
Raman, Jayalakshmi;Fritz, Timothy A.;Tabak, Lawrence A.
通讯作者：
Tabak, Lawrence A.
影响因子：
32.4
作者：
Posey AD Jr;Schwab RD;Boesteanu AC;Steentoft C;Mandel U;Engels B;Stone JD;Madsen TD;Schreiber K;Haines KM;Cogdill AP;Chen TJ;Song D;Scholler J;Kranz DM;Feldman MD;Young R;Keith B;Schreiber H;Clausen H;Johnson LA;June CH
通讯作者：
June CH