Science:生长激素受体，也是癌症和糖尿病的治疗靶标

          

      近日，昆士兰大学科学家们发现，一种调节你长多高的蛋白可用于治疗疾病，包括癌症和糖尿病。生长激素通过其受体作用，决定是否你正在努力达到身高最高。

来自昆士兰大学分子生物科学研究所Mike Waters教授的研究，现在已经发现生长激素受体也是癌症和糖尿病药物靶标。

 

没有生长激素受体的人从不罹患癌症或糖尿病死亡，这使它成为理想的药物靶标，Waters教授说：但我们只有足够了解它是如何运作的，才能设计出癌症或糖尿病药物。

 

新研究现在已经发现了生长激素如何在分子水平上打开其受体。这一发现发表在Science杂志上。博士Andrew Brooks说，这一发现不止对癌症和糖尿病有影响。

 

生长激素受体是一组被称为细胞因子受体的蛋白中的一个，细胞因子受体用于治疗对一系列疾病包括炎症性肠道疾病，血液病，骨质疏松症和肥胖。生长激素受体如何发挥功能让研究人员能更好洞察到其他细胞因子受体是如何工作的，这反过来将有助开发针对这些细胞因子受体的治疗方法。

原文链接

Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor

Andrew J. Brooks, et al.

Class I cytokines regulate key processes such as growth, lactation, hematopoiesis, and immune function and contribute to oncogenesis. Although the extracellular domain structures of their receptors are well characterized, little is known about how the receptors activate their associated JAK (Janus kinase) protein kinases. We provide a mechanistic description for this process, focusing on the growth hormone (GH) receptor and its associated JAK2.

 

Rationale

 

We tested whether the receptor exists as a dimer in the inactive state by homo-FRET [fluorescence resonance energy transfer (FRET) between the proteins labeled with the same fluorophore] and other means. Then, to define receptor movements resulting from activation, we attached FRET reporters to the receptor below the cell membrane and correlated their movement with receptor activation, measured as increased cell proliferation. We controlled the position of the transmembrane helices with leucine zippers and mutagenesis, and we again monitored FRET and receptor activation. We used cysteine cross-linking data to define the faces of the transmembrane helices in contact in the basal state and verified this with molecular dynamics, which allowed us to model the activation process. We also used FRET reporters to monitor the movement of JAK2, and we matched this with molecular dynamics docking of the crystal structures of the kinase and its pseudokinase domains to derive a model for activation, which we then verified experimentally.

Results

 

We found that the GH receptor exists predominantly as a dimer in vivo, held together by its transmembrane helices. These helices are parallel in the basal state, and binding of the hormone converts them into a left-hand crossover state that induces separation of helices at the lower transmembrane boundary (hence, Box1 separation). This movement is triggered by increased proximity of the juxtamembrane sequences, a consequence of locking together of the lower module of the extracellular domain on hormone binding. This movement is triggered by increased proximity of the juxtamembrane sequences , a Both this locking and the helix state transition require rotation of the receptors, but the key outcome is separation of the Box1 sequences. Because these sequences are bound to the JAK2 FERM (4.1, ezrin, radixin, moesin) domains, this separation results in removal of the pseudokinase inhibitory domain of one JAK2, which is blocking the kinase domain of the other JAK2, and vice versa. This brings the two kinase domains into productive apposition, triggering JAK2 activation. We verified this mechanism by kinase-pseudokinase domain swap, by changes in JAK2 FRET signal on activation, by showing association of pseudokinase-kinase domain pairs, and by docking of the crystal structures. An animation of our complete model of GH receptor activation is provided at http://web-services.imb.uq.edu.au/waters/hgh.html.

Conclusion

 

The proposed mechanism will be useful in understanding the many actions of GH, which include altered growth, metabolism, and bone turnover. We expect that it may extend to other members of this important receptor family. The mechanism provides a molecular basis for understanding the oncogenic JAK2 mutations responsible for polycythemia vera and certain other hematologic disorders and may thus be of value in the design of small-molecule inhibitors of clinical applicability.