转化生长因子-β受体β-聚糖的结合特性：受体复合物组装和信号增强的拟议机制。,Biochemistry

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转化生长因子-β受体β-聚糖的结合特性：受体复合物组装和信号增强的拟议机制。
Biochemistry ( IF 2.9 ) Pub Date : 2016-12-02 00:00:00 , DOI: 10.1021/acs.biochem.6b00566
Maria M. Villarreal , Sun Kyung Kim , Lindsey Barron , Ravi Kodali ₁ , Jason Baardsnes ₂ , Cynthia S. Hinck ₁ , Troy C. Krzysiak ₁ , Morkos A. Henen ₁ , Olga Pakhomova , Valentín Mendoza ₃ , Maureen D. O’Connor-McCourt ₂ , Eileen M. Lafer , Fernando López-Casillas ₃ , Andrew P. Hinck ₁

Affiliation

转化生长因子（TGF）β1，β2和β3（分别为TGF-β1-TGF-β3）是分泌的小信号蛋白，它们各自通过TGF-βI型和II型受体（分别为TβRI和TβRII）发出信号。但是，众所周知，TGF-β2与TGF-β1和TGF-β3的结合强度比TGF-β1和TGF-β3弱数百倍，它对β-聚糖（膜锚定的非信号受体）有额外的要求。Betaglycan具有两个在独立位点结合TGF-β2的结构域，但是它如何结合TGF-β2以增强TβRII的结合以及与TGF-β，TβRII和betaglycan的复合物如何转变为与TGF-β，TβRII的信号复合物和TβRI不了解。为了研究其机制，TGF-β与β聚糖胞外域的结合以及其两个独立的结合域，使用表面等离振子共振，等温滴定量热法和尺寸排阻色谱法研究了直接或与TβRI和TβRII胞外域结合使用的方法。这些研究表明，β-聚糖以一种化学计量比1：1结合TGF-β同型二聚体，其方式是允许一分子TβRII结合。这些研究进一步表明，β-聚糖适度增强了TβRII的结合，必须进行置换才能使TβRI结合。这些发现表明，β-聚糖的功能是将TGF-β2结合并浓缩在细胞表面，从而通过膜定位作用和变构作用促进TβRII的结合。这些研究进一步表明，向信号复合物的转化是由TβRI的募集介导的，

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Binding Properties of the Transforming Growth Factor-β Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling

Transforming growth factor (TGF) β1, β2, and β3 (TGF-β1–TGF-β3, respectively) are small secreted signaling proteins that each signal through the TGF-β type I and type II receptors (TβRI and TβRII, respectively). However, TGF-β2, which is well-known to bind TβRII several hundred-fold more weakly than TGF-β1 and TGF-β3, has an additional requirement for betaglycan, a membrane-anchored nonsignaling receptor. Betaglycan has two domains that bind TGF-β2 at independent sites, but how it binds TGF-β2 to potentiate TβRII binding and how the complex with TGF-β, TβRII, and betaglycan undergoes the transition to the signaling complex with TGF-β, TβRII, and TβRI are not understood. To investigate the mechanism, the binding of the TGF-βs to the betaglycan extracellular domain, as well as its two independent binding domains, either directly or in combination with the TβRI and TβRII ectodomains, was studied using surface plasmon resonance, isothermal titration calorimetry, and size-exclusion chromatography. These studies show that betaglycan binds TGF-β homodimers with a 1:1 stoichiometry in a manner that allows one molecule of TβRII to bind. These studies further show that betaglycan modestly potentiates the binding of TβRII and must be displaced to allow TβRI to bind. These findings suggest that betaglycan functions to bind and concentrate TGF-β2 on the cell surface and thus promote the binding of TβRII by both membrane-localization effects and allostery. These studies further suggest that the transition to the signaling complex is mediated by the recruitment of TβRI, which simultaneously displaces betaglycan and stabilizes the bound TβRII by direct receptor–receptor contact.

更新日期：2016-12-02

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