Internal cleavage and synergy with twisted gastrulation enhance BMP inhibition by BMPER.
Internal cleavage and synergy with twisted gastrulation enhance BMP inhibition by BMPER.
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DOI：
10.1016/j.matbio.2018.08.006
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Baldock C
中科院分区：
文献类型：
--
作者：
Lockhart-Cairns MP;Lim KTW;Zuk A;Godwin ARF;Cain SA;Sengle G;Baldock C
骨形态发生蛋白（BMP）是参与发育和病理过程的重要信号分子，在基质中受分泌糖蛋白的调节。一种这样的调节剂是BMP结合内皮细胞趋化因子衍生的调节剂（BMPER），其可以以上下文和浓度依赖性方式抑制和增强BMP信号传导。扭曲原肠胚形成（Tsg）也可以促进或消除BMP活性，但目前还不清楚Tsg和BMPER是否直接相互作用，从而对BMP信号转导发挥协同作用。在这里，我们表明，人类BMPER结合Tsg通过N-末端BMP结合区，单独更有力地抑制BMP-4信号比全长BMPER。此外，BMPER和Tsg协同抑制BMP-4信号传导，表明协同功能以抑制BMP活性。此外，全长BMPER通过其C-末端区域与细胞表面硫酸乙酰肝素蛋白聚糖的结合靶向质膜，但活性切割片段是可扩散的。小角X射线散射和电子显微镜显示，BMPER具有细长的构象，允许N-末端BMP结合和C-末端细胞相互作用区域在空间上分离。为了深入了解BMPER生物利用度的内部切割，致病BMPER点突变，P370 L，以前确定的酸催化裂解位点，被引入。突变蛋白被分泌，但突变阻止了细胞内切割，导致缺乏生物活性切割片段。此外，突变体BMPER在下游位点被细胞外切割，推测是由于突变而变得可用。这种对细胞外蛋白酶的易感性和生物活性N末端切割片段的丧失可能导致疾病中BMPER功能的丧失。BMPER和Tsg协同工作以增加BMP 4信号传导的抑制。N-末端BMPER切割产物是BMP 4活性的更有效的抑制剂。BMPER是细长的和柔性的，具有不同的BMP-和HS-结合区域。引起疾病的BMPER点突变阻止内部自催化裂解。
Bone morphogenetic proteins (BMPs) are essential signalling molecules involved in developmental and pathological processes and are regulated in the matrix by secreted glycoproteins. One such regulator is BMP-binding endothelial cell precursor-derived regulator (BMPER) which can both inhibit and enhance BMP signalling in a context and concentration-dependent manner. Twisted gastrulation (Tsg) can also promote or ablate BMP activity but it is unclear whether Tsg and BMPER directly interact and thereby exert a synergistic function on BMP signalling. Here, we show that human BMPER binds to Tsg through the N-terminal BMP-binding region which alone more potently inhibits BMP-4 signalling than full-length BMPER. Additionally, BMPER and Tsg cooperatively inhibit BMP-4 signalling suggesting a synergistic function to dampen BMP activity. Furthermore, full-length BMPER is targeted to the plasma membrane via binding of its C-terminal region to cell surface heparan sulphate proteoglycans but the active cleavage fragment is diffusible. Small-angle X-ray scattering and electron microscopy show that BMPER has an elongated conformation allowing the N-terminal BMP-binding and C-terminal cell-interactive regions to be spatially separated. To gain insight into the regulation of BMPER bioavailability by internal cleavage, a disease-causing BMPER point mutation, P370L, previously identified in the acid-catalysed cleavage site, was introduced. The mutated protein was secreted but the mutation prevented intracellular cleavage resulting in a lack of bioactive cleavage fragment. Furthermore, mutant BMPER was extracellularly cleaved at a downstream site presumably becoming available due to the mutation. This susceptibility to extracellular proteases and loss of bioactive N-terminal cleavage fragment may result in loss of BMPER function in disease. BMPER and Tsg work in concert to increase the inhibition of BMP4 signalling. The N-terminal BMPER cleavage product is a more potent inhibitor of BMP4 activity. BMPER is elongated and flexible with distinct BMP- and HS-binding regions. A disease causing BMPER point mutation prevents internal auto-catalytic cleavage.
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影响因子：
3.4
作者：
Schuck, P
通讯作者：
Schuck, P
影响因子：
6.7
作者：
Moser, M;Patterson, C
通讯作者：
Patterson, C
DOI：
10.1083/jcb.200808064
发表时间：
2009-02-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kelley R;Ren R;Pi X;Wu Y;Moreno I;Willis M;Moser M;Ross M;Podkowa M;Attisano L;Patterson C
通讯作者：
Patterson C
影响因子：
3
作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE
影响因子：
6.1
作者：
Petoukhov MV;Franke D;Shkumatov AV;Tria G;Kikhney AG;Gajda M;Gorba C;Mertens HD;Konarev PV;Svergun DI
通讯作者：
Svergun DI