Structural Determination of the E-Related Region of the TGFbeta type III receptor

TGFbeta III 型受体 E 相关区域的结构测定

• 批准号: 7332793
• 负责人: THOMAS KEENAN MILLSTEAD
• 金额: $ 3.65万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7332793
• 关键词: Affinity; Amino Acids; Binding; Binding Sites; C-terminal; Cleaved cell; Cleft Palate; Complement; Complex; Condition; Crystallization; Crystallography; Development; Distal; Electrophoretic Mobility Shift Assay; Endoglin; Extracellular Domain; Growth Factor; Hand; Human; Knockout Mice; Label; Ligand Binding; Membrane; N-terminal; NMR Spectroscopy; Odontogenic Tumors; Phosphorylation; Play; Protein Isoforms; Proteoglycan; Range; Recruitment Activity; Role; Sampling; Series; Side; Signal Transduction; Site-Directed Mutagenesis; Solutions; Structure; Surface Plasmon Resonance; TGF beta type III receptor; TGFB1 gene; TGFB2 gene; Tooth structure; Transforming Growth Factor beta; Transmembrane Domain; UMOD gene; Vertebral column; craniofacial; extracellular; inhibin; insight; member; polypeptide; receptor; research study; three dimensional structure; tumorigenesis

DESCRIPTION (provided by applicant): The transforming growth factor beta (TGF?) superfamily is composed of 42 structurally related polypeptide growth factors that perform various functions in humans. All of the members of the TGF3 superfamily signal through a distinct set of extracellular receptors commonly known as the type I and type II receptors. The prototypic members of the superfamily are the TGF?s: TGFB?1, 2, and 3. Signaling is initiated when the igand binds to the type II receptor with subsequent recruitment of the type I receptor forming the mature signaling complex. Both TGF?1 and 3 have intrinsically high affinity for the type II receptor (T?RII) and are able to initiate signaling without any assistance. TGF?2, on the other hand, binds very weakly to the type II receptor. The intrinsically low binding affinity of TGF?2 for TBRII is compensated through the use of an accessory receptor, betaglycan. Betaglycan's role in TGF?2 signaling is to present TGF?2 to T?RII by increasing the intrinsically low affinity of TGF?2 for T(3RII through the formation of a TGF?2:betaglycan:TBRII ternary complex. The TGF? type I receptor (T?RI) is recruited to the complex, betaglycan is displaced, forming the mature signaling complex. Although it is known that betaglycan is required for TGF?2 signaling, the mechanism of complex assembly is not. Betaglycan's extracellular domain is composed of two separate sub-domains, each capable of promoting TGF(3 induced rSMAD phosphorylation. Implying that each half of the extracellular domain betaglycan can independently present TGF?2 to T?RII. The membrane-distal half is referred to as the endoglin-related region (BGE) and the membrane-proximal half is referred to as uromodulin-related region (BGU). While both regions are able to bind TGFB, BGU is also capable of binding inhibin. In combination with the fact that inhibin binding is solely restricted to BGU, it also implies that each half may play a different role in TGF 3 signaling. BGE was selected for study since it is solely capable promoting TGF?2 signaling. To further our understanding of betaglycan's mechanism of presentation, the solution structure of the Endoglin-related region of betaglycan (BGE) will be determined using solution NMR spectroscopy with the complementing crystal structure of BGE in complex with TGFB2 and T?RII. In parallel, native gel shift assays and surface plasmon resonance binding studies will be used to examine the influence BGE has on the binding of T?RII. TGF?2 has been found to play crucial roles in tooth development, it has also been implicated in tumorigenesis of odontogenic neoplasms, and TGF?2 knockout mice develop cleft palate. Understanding the structural and functional role betaglycan plays in TGF(32 signaling, it will give vital insight into craniofacial development.

描述（申请人提供）：转化生长因子β（TGF？）超家族由42种结构上相关的多肽生长因子组成，它们在人体内发挥各种功能。TGF β超家族的所有成员都通过一组不同的细胞外受体（通常称为I型和II型受体）发出信号。超家族的原型成员是TGF？s：TGFB？1、2和3。当配体与II型受体结合时，信号传导开始，随后募集I型受体形成成熟的信号传导复合物。两个TGF？1和3对II型受体（T？RII），并且能够在没有任何帮助的情况下发起信令。转化生长因子另一方面，2与II型受体的结合非常弱。本质上低结合亲和力的TGF？通过使用辅助受体β聚糖来补偿TBRII的2。Betaglycan在TGF中的作用？2信号转导途径是提呈TGF？2、T？RII通过增加固有的低亲和力TGF？2为T（3RII通过形成TGF？2：β聚糖：TBRII三元复合物。TGF？I型受体（T？RI）被募集到复合物中，β聚糖被置换，形成成熟的信号传导复合物。虽然它是已知的，β聚糖是TGF？2信号，复杂的组装机制是没有的。β聚糖的胞外结构域由两个独立的亚结构域组成，每个亚结构域都能够促进TGF β诱导的rSMAD磷酸化。这意味着每一半的胞外结构域β聚糖可以独立地提出TGF？2、T？RII.膜远端的一半被称为内皮素相关区（BGE），膜近端的一半被称为尿调蛋白相关区（BGU）。虽然这两个区域都能够结合TGFB，但BGU也能够结合TGFBin。结合BGU结合仅限于BGU的事实，这也意味着每一半可能在TGF β 3信号传导中发挥不同的作用。选择BGE进行研究，因为它是唯一能够促进TGF？2信号为了进一步我们的理解β聚糖的机制介绍，溶液结构的内皮相关区域的β聚糖（BGE）将确定使用溶液NMR光谱与补充晶体结构的BGE在复杂的TGFB2和T？RII.在平行，天然凝胶位移测定和表面等离子体共振结合的研究将被用来检查的影响BGE的结合T？RII.转化生长因子2已被发现在牙齿发育中起着至关重要的作用，它也被牵连在牙源性肿瘤的肿瘤发生，和TGF？2只基因敲除小鼠出现腭裂。了解β聚糖在TGF β 2信号传导中的结构和功能作用，将对颅面发育提供重要的见解。