Department of Chemistry & Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
Nat Chem Biol. 2011 Jan;7(1):51-7. doi: 10.1038/nchembio.494. Epub 2010 Dec 5.
Proline switches, controlled by cis-trans isomerization, have emerged as a particularly effective regulatory mechanism in a wide range of biological processes. Here we report the structures of both the cis and trans conformers of a proline switch in the Crk signaling protein. Proline isomerization toggles Crk between two conformations: an autoinhibitory conformation, stabilized by the intramolecular association of two tandem SH3 domains in the cis form, and an uninhibited, activated conformation promoted by the trans form. In addition to acting as a structural switch, the heterogeneous proline recruits cyclophilin A, which accelerates the interconversion rate between the isomers, thereby regulating the kinetics of Crk activation. The data provide atomic insight into the mechanisms that underpin the functionality of this binary switch and elucidate its remarkable efficiency. The results also reveal new SH3 binding surfaces, highlighting the binding versatility and expanding the noncanonical ligand repertoire of this important signaling domain.
脯氨酸开关通过顺反异构控制，已成为广泛的生物学过程中一种特别有效的调控机制。在这里，我们报告了 Crk 信号蛋白中脯氨酸开关的顺式和反式构象的结构。脯氨酸异构化使 Crk 在两种构象之间转换：一种是自体抑制构象，在顺式中两个串联 SH3 结构域的分子内缔合稳定；另一种是无抑制、激活构象，由反式促进。除了作为结构开关外，异构脯氨酸还招募亲环素 A，从而加速异构体之间的互变速度，从而调节 Crk 激活的动力学。这些数据提供了原子水平的见解，揭示了这个二元开关功能的机制，并阐明了其显著的效率。结果还揭示了新的 SH3 结合表面，突出了该重要信号结构域的结合多功能性和扩大的非经典配体库。
