Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe(2+)-binding.
Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe(2+)-binding.
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DOI：
10.1038/s41467-018-02859-z
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发表时间：
2018-02-06
影响因子：
16.6
通讯作者：
Kurie JM
中科院分区：
文献类型：
--
作者：
Guo HF;Tsai CL;Terajima M;Tan X;Banerjee P;Miller MD;Liu X;Yu J;Byemerwa J;Alvarado S;Kaoud TS;Dalby KN;Bota-Rabassedas N;Chen Y;Yamauchi M;Tainer JA;Phillips GN Jr;Kurie JM
胶原赖氨酸羟基酶(LH1-3)是依赖于Fe2+和2-氧戊二酸(2-OG)的加氧酶，维持细胞外基质的动态平衡。高LH2水平会导致稳定的胶原交联物积累，从而促进纤维化和癌症进展。然而，开发黄体生成素拮抗剂将需要结构上的洞察力。在这里，我们报道了多食棘阿米巴模拟病毒L230的L230的LH域的2 ä晶体结构和二聚体组装的X射线散射。双链β-螺旋核心中的环残基产生尾到尾的二聚体。稳定的疏水性亮氨酸锁定在相对亚基上的芳香酪氨酸口袋中。激活场地空间坐标空间坐标为Fe2+。这两个活性部位位于一个深表面裂隙的两侧，这表明二聚化作用产生了一个胶原结合部位。失去Fe2+结合会破坏二聚体。裂隙中二聚体的破坏和电荷反转增加了Km，降低了Lh的活性。L230在肿瘤中的异位表达促进了胶原的交联和转移。这些见解表明，抑制剂是治疗纤维化和癌症的靶点。胶原蛋白赖氨酸羟基酶促进癌症进展。本文报道了多食棘阿米巴模拟病毒L230的赖氨酰羟基酶结构域的晶体结构，该结构对开发促黄体生成素抑制剂很有意义，并表明L230在肿瘤中的异位表达促进了胶原的交联和转移。
Collagen lysyl hydroxylases (LH1-3) are Fe2+- and 2-oxoglutarate (2-OG)-dependent oxygenases that maintain extracellular matrix homeostasis. High LH2 levels cause stable collagen cross-link accumulations that promote fibrosis and cancer progression. However, developing LH antagonists will require structural insights. Here, we report a 2 Å crystal structure and X-ray scattering on dimer assemblies for the LH domain of L230 in Acanthamoeba polyphaga mimivirus. Loop residues in the double-stranded β-helix core generate a tail-to-tail dimer. A stabilizing hydrophobic leucine locks into an aromatic tyrosine-pocket on the opposite subunit. An active site triad coordinates Fe2+. The two active sites flank a deep surface cleft that suggest dimerization creates a collagen-binding site. Loss of Fe2+-binding disrupts the dimer. Dimer disruption and charge reversal in the cleft increase Km and reduce LH activity. Ectopic L230 expression in tumors promotes collagen cross-linking and metastasis. These insights suggest inhibitor targets for fibrosis and cancer. Collagen lysyl hydroxylases promote cancer progression. Here the authors present the crystal structure of the lysyl hydroxylase domain of L230 from Acanthamoeba polyphaga mimivirus, which is of interest for LH inhibitor development, and show that ectopic expression of L230 in tumors promotes collagen cross-linking and metastasis.
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影响因子：
11.8
作者：
Dare RK;Chittaganpitch M;Erdman DD
通讯作者：
Erdman DD
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：
6.9
作者：
Heikkinen, Jari;Risteli, Maija;Myllyla, Raili
通讯作者：
Myllyla, Raili
影响因子：
16.6
作者：
Ahmed Z;Timsah Z;Suen KM;Cook NP;Lee GR 4th;Lin CC;Gagea M;Marti AA;Ladbury JE
通讯作者：
Ladbury JE
影响因子：
5.7
作者：
Horita, Shoichiro;Scotti, John S.;Thinnes, Cyrille;Mottaghi-Taromsari, Yousef S.;Thalhammer, Armin;Ge, Wei;Aik, WeiShen;Loenarz, Christoph;Schofield, Christopher J.;McDonough, Michael A.
通讯作者：
McDonough, Michael A.