Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting.
Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting.
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DOI：
10.1038/s41467-018-03370-1
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发表时间：
2018-03-08
影响因子：
16.6
通讯作者：
Overduin M
中科院分区：
文献类型：
--
作者：
Lenoir M;Ustunel C;Rajesh S;Kaur J;Moreau D;Gruenberg J;Overduin M
分类连接蛋白通过结合磷脂将运输机器锚在膜上。该超家族的范式是分选连接蛋白3（SNX 3），它通过识别3-磷酸磷脂酰肌醇（PI 3 P）定位于早期核内体，以启动逆转录酶介导的货物分离至反式高尔基体网络（TGN）。在这里，我们报告的解决方案的全长人SNX 3的结构，并显示PI 3 P识别伴随着双层插入近端环在其扩展的Phox同源（PX）域。磷酸肌醇（PIP）结合被立体特异性PI 3 P口袋旁边的保守丝氨酸的癌症相关磷酸化完全阻断。这种“PIP终止”将内体SNX 3释放到胞质溶胶中，并揭示了蛋白激酶如何控制膜组装。它构成了在PX超家族和包括真菌和植物在内的整个进化过程中发现的广泛的调节元件。这阐明了生物开关的机制，从而结构化PIP位点被磷酸化以从细胞器表面释放蛋白质机器。分选连接蛋白3（SNX 3）是定位于早期内体的磷脂酰肌醇3-磷酸结合蛋白。在这里，作者使用NMR来解析SNX 3的膜相互作用，揭示了膜结合是通过其脂质识别位点对保守丝氨酸的磷酸化来调节的。
Sorting nexins anchor trafficking machines to membranes by binding phospholipids. The paradigm of the superfamily is sorting nexin 3 (SNX3), which localizes to early endosomes by recognizing phosphatidylinositol 3-phosphate (PI3P) to initiate retromer-mediated segregation of cargoes to the trans-Golgi network (TGN). Here we report the solution structure of full length human SNX3, and show that PI3P recognition is accompanied by bilayer insertion of a proximal loop in its extended Phox homology (PX) domain. Phosphoinositide (PIP) binding is completely blocked by cancer-linked phosphorylation of a conserved serine beside the stereospecific PI3P pocket. This “PIP-stop” releases endosomal SNX3 to the cytosol, and reveals how protein kinases control membrane assemblies. It constitutes a widespread regulatory element found across the PX superfamily and throughout evolution including of fungi and plants. This illuminates the mechanism of a biological switch whereby structured PIP sites are phosphorylated to liberate protein machines from organelle surfaces. Sorting nexin 3 (SNX3) is a phosphatidylinositol 3-phosphate binding protein that localizes to early endosomes. Here the authors use NMR to resolve SNX3′s membrane interactions, revealing that membrane binding is regulated through phosphorylation of a conserved serine by its lipid recognition site.
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影响因子：
4.8
作者：
Cozier, GE;Carlton, J;Cullen, PJ
通讯作者：
Cullen, PJ
DOI：
10.1073/pnas.0607084104
发表时间：
2007-02-13
影响因子：
11.1
作者：
Chi, An;Huttenhower, Curtis;Hunt, Donald F.
通讯作者：
Hunt, Donald F.
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
通讯作者：
BAX, A
DOI：
10.1139/bcb-2014-0074
发表时间：
2014-12
期刊：
Biochemistry and cell biology = Biochimie et biologie cellulaire
影响因子：
--
作者：
Kufareva I;Lenoir M;Dancea F;Sridhar P;Raush E;Bissig C;Gruenberg J;Abagyan R;Overduin M
通讯作者：
Overduin M