Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors
Monika A. Davare, Nadeem A. Vellore, Jacob P. Wagner, Christopher A. Eide, James R. Goodman, Alexander Drilon, Michael W. Deininger, Thomas O’Hare, and Brian J. Druker
Targeting oncogenic ROS1 fusion proteins with crizotinib has shown promising clinical outcomes in non-small cell lung cancer (NSCLC) patients, but emergence of resistance to therapy has been reported. By profiling the activity of clinically viable ROS1/anaplastic lymphoma kinase (ALK) inhibitors, we discovered that the Food and Drug Administration (FDA)-approved inhibitor cabozantinib potently inhibits native ROS1 and the crizotinib-resistant ROS1G2032R mutant, suggesting potential utility for treatment of ROS1-rearranged lung cancer. Notably, cabozantinib is ineffective against the closely related ALK kinase. Molecular modeling shows specific structural differences between the kinase domains of ROS1 and ALK that explain selective binding of cabozantinib to ROS1. These findings reveal limitations pertaining to the widely presumed inhibitory reciprocity of ROS1 and ALK inhibitors and may facilitate rational design of new ROS1-selective inhibitors. (See pp. E5381–E5390.)
Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP
Nikita Vasilyev, Anna Polonskaia, Jennifer C. Darnell, Robert B. Darnell, Dinshaw J. Patel, and Alexander Serganov
The arginine-glycine-rich (RGG) box is an abundant RNA-binding motif present in many proteins. The RGG motif of the Fragile Mental Retardation Protein (FMRP) specifically binds guanine-quadruplex-containing RNA. Using X-ray crystallography, we uncovered molecular principles that account for specificity and affinity of the interactions between the RGG motif and guanine-quadruplex-containing RNA. The structure-based biochemical assays revealed that specific recognition of the RNA extends to the duplex region, thus identifying a broad network of important RNA–protein interactions and suggesting a common RNA binding principle for other RGG motif-containing proteins. (See pp. E5391–E5400.)
Identification of the VERNALIZATION 4 gene reveals the origin of spring growth habit in ancient wheats from South Asia
Nestor Kippes, Juan M. Debernardi, Hans A. Vasquez-Gross, Bala A. Akpinar, Hikment Budak, Kenji Kato, Shiaoman Chao, Eduard Akhunov, and Jorge Dubcovsky
A precise regulation of flowering time is critical for plant reproductive success and for cereal crops to maximize grain production. In wheat, barley, and other temperate cereals, vernalization genes play an important role in the acceleration of reproductive development after long periods of low temperatures during the winter (vernalization). In this study, we identified VERNALIZATION 4 (VRN-D4), a vernalization gene that was critical for the development of spring growth habit in the ancient wheats from South Asia. We show that mutations in regulatory regions of VRN-D4 are shared with other VRN-A1 alleles and can be used to modulate the vernalization response. These previously unknown alleles provide breeders new tools to engineer wheat varieties better adapted to different or changing environments. (See pp. E5401–E5410.)
Breeding signatures of rice improvement revealed by a genomic variation map from a large germplasm collection
Weibo Xie (谢为博), Gongwei Wang (王功伟), Meng Yuan, Wen Yao, Kai Lyu, Hu Zhao, Meng Yang, Pingbo Li, Xing Zhang, Jing Yuan, Quanxiu Wang, Fang Liu, Huaxia Dong, Lejing Zhang, Xinglei Li, Xiangzhou Meng, Wan Zhang, Lizhong Xiong, Yuqing He, Shiping Wang, Sibin Yu, Caiguo Xu, Jie Luo, Xianghua Li, Jinghua Xiao, Xingming Lian (练兴明), and Qifa Zhang (张启发)
Intensive rice breeding over the past 50 y has produced many high-performing cultivars, but our knowledge of the genomic changes associated with such improvement remains limited. By analyzing sequences of 1,479 rice accessions, this study identified genomic changes associated with breeding efforts, referred to as breeding signatures, involving 7.8% of the rice genome. Accumulation of selected regions is positively correlated with yield improvement. The number of selected regions in a line may be used for predicting agronomic potential, and the selected loci may provide useful targets for rice improvement. (See pp. E5411–E5419.)
Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia
Minfeng Shu, Te Du, Grace Zhou, and Bernard Roizman
A major unresolved issue confronting infectious diseases is the mechanism by which virulent, potentially lethal viruses remain silent (latent) in selected cells in the human body until induced to replicate and spread in response to stress. The establishment of latent infection by herpes simplex viruses in sensory or autonomic neurons is a common event in a large fraction of the human population. Here we report that activating transcription factor 3 (ATF3) is induced by stress both in infected cells in culture and in ganglia harboring latent virus. The function of ATF3 is to block the reactivation of virus induced by neuronal stress. (See pp. E5420–E5426.)
Transcellular spreading of huntingtin aggregates in the Drosophila brain
Daniel T. Babcock and Barry Ganetzky
Propagation of protein aggregates throughout the nervous system is thought to play a significant role in the pathology of neurodegenerative diseases. Thus, understanding how this propagation is regulated is crucial for identifying potential therapeutic interventions. Here we use experimental advantages of Drosophila to investigate aggregate spreading. We demonstrate that huntingtin, containing an expanded polyglutamine tract of 138 repeats, but not an unexpanded form, aggregates and spreads rapidly throughout the brain, resulting in loss of vulnerable neurons. Aggregate spreading and neuronal loss are impaired by blocking synaptic exocytosis in releasing cells or endocytic uptake in target cells. These studies enable screens for genetic and pharmacological modifiers that could ameliorate the deleterious effects of spreading in neurodegenerative diseases. (See pp. E5427–E5433.)
Genetic variation in CD38 and breastfeeding experience interact to impact infants’ attention to social eye cues
Kathleen M. Krol, Mikhail Monakhov, Poh San Lai, Richard P. Ebstein, and Tobias Grossmann
Maternal care plays an important role in the development of the offspring’s social behaviors through the programming of relevant neural and hormonal systems. However, it is unclear how specific maternal behaviors, such as breastfeeding and genetic variation related to the oxytocin system, contribute to emerging social behaviors in human infants. We therefore examined infants’ attention to emotional eyes. Our results revealed that infants with the genotype previously associated with decreased availability of oxytocin and an increased rate of autism were most affected by extended durations of exclusive breastfeeding. Namely, these infants showed increased attention to happy eyes and decreased attention to angry eyes. This finding suggests that breastfeeding experience enhances prosocial tendencies in infants that are genetically at risk for autism. (See pp. E5434–E5442.)