Mechanism and evolution of the Zn-fingernail required for interaction of VARP with VPS29.
Mechanism and evolution of the Zn-fingernail required for interaction of VARP with VPS29.
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DOI：
10.1038/s41467-020-18773-2
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发表时间：
2020-10-06
影响因子：
16.6
通讯作者：
Owen DJ
中科院分区：
文献类型：
--
作者：
Crawley-Snowdon H;Yang JC;Zaccai NR;Davis LJ;Wartosch L;Herman EK;Bright NA;Swarbrick JS;Collins BM;Jackson LP;Seaman MNJ;Luzio JP;Dacks JB;Neuhaus D;Owen DJ
VARP和TBC 1D 5是逆转录酶介导的内体逆向运输的辅助/调节蛋白。使用NMR/X-射线的方法，我们确定了retromer亚基VPS 29和一个12个残基，四个半胱氨酸/Zn++微结构域，我们称之为锌指甲，其中两个是存在于VARP之间的复合物的结构。破坏VPS 29：VARP结合的突变抑制从内体到细胞表面的运输。我们表明，VARP和TBC 1D 5结合VPS 29上的相同位点，并且可以在体内竞争结合VPS 29。VPS 29在异源六聚体、膜连接的逆转录体弓中的相对配置表明，VARP将通过同时结合两个VPS 29而优选结合到组装的逆转录体涂层。TBC 1D 5：VPS 29相互作用已经有超过10亿年的历史，但是锌指甲仅出现在直接产生动物的谱系中的VARP同源物中，此时逆转录酶/VARP/TBC 1D 5调控网络完全建立。VARP结合于内体并作为蛋白质：蛋白质相互作用平台发挥作用。在这里，作者提出了逆转子亚基VPS 29和VARP锌指甲微结构域之间的复合物的NMR结构，该结构域在结构上不同于锌指，并进一步表明，消除VPS 29的突变：VARP结合，抑制从内体到细胞表面的运输。
VARP and TBC1D5 are accessory/regulatory proteins of retromer-mediated retrograde trafficking from endosomes. Using an NMR/X-ray approach, we determined the structure of the complex between retromer subunit VPS29 and a 12 residue, four-cysteine/Zn++ microdomain, which we term a Zn-fingernail, two of which are present in VARP. Mutations that abolish VPS29:VARP binding inhibit trafficking from endosomes to the cell surface. We show that VARP and TBC1D5 bind the same site on VPS29 and can compete for binding VPS29 in vivo. The relative disposition of VPS29s in hetero-hexameric, membrane-attached, retromer arches indicates that VARP will prefer binding to assembled retromer coats through simultaneous binding of two VPS29s. The TBC1D5:VPS29 interaction is over one billion years old but the Zn-fingernail appears only in VARP homologues in the lineage directly giving rise to animals at which point the retromer/VARP/TBC1D5 regulatory network became fully established. VARP is bound to endosomes and functions as a protein:protein interaction platform. Here, the authors present the NMR structure of the complex between the retromer subunit VPS29 and a VARP Zn-fingernail microdomain that is structurally distinct from Zn-fingers and further show that mutations, which abolish VPS29:VARP binding, inhibit trafficking from endosomes to the cell surface.
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影响因子：
9.2
作者：
Bright, Nicholas A.;Davis, Luther J.;Luzio, J. Paul
通讯作者：
Luzio, J. Paul
DOI：
10.1083/jcb.201605090
发表时间：
2016-08-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dennis MK;Delevoye C;Acosta-Ruiz A;Hurbain I;Romao M;Hesketh GG;Goff PS;Sviderskaya EV;Bennett DC;Luzio JP;Galli T;Owen DJ;Raposo G;Marks MS
通讯作者：
Marks MS
影响因子：
4.4
作者：
Vedovato M;Rossi V;Dacks JB;Filippini F
通讯作者：
Filippini F
影响因子：
16.8
作者：
Collins, BM;Skinner, CF;Owen, DJ
通讯作者：
Owen, DJ
影响因子：
11.8
作者：
Hesketh, Geoffrey G.;Perez-Dorado, Inmaculada;Jackson, Lauren R.;Wartosch, Lena;Schaefer, Ingmar B.;Gray, Sally R.;McCoy, Airlie J.;Zeldin, Oliver B.;Garman, Elspeth F.;Harbour, Michael E.;Evans, Philip R.;Seaman, Matthew N. J.;Luzio, J. Paul;Owen, David J.
通讯作者：
Owen, David J.