Bipartite Role of Hsp90 Keeps CRAF Kinase Poised for Activation [Protein Structure and Folding]
October 5th, 2016 by Mitra, S., Ghosh, B., Gayen, N., Roy, J., Mandal, A. K.
CRAF kinase maintains cell viability, growth and proliferation by participating in MAPK pathway. Unlike BRAF, CRAF requires continuous chaperoning by Hsp90 to retain MAPK signaling. But, the reason behind the continuous association of Hsp90 with CRAF is still elusive. In this study, we have identified the bipartite role of Hsp90 in chaperoning CRAF kinase. Hsp90 facilitates Ser-621 phosphorylation of CRAF and prevents the kinase from degradation. Co-chaperone Cdc37 assists in this phosphorylation event. However, after folding the stability of the kinase becomes insensitive to Hsp90 inhibition, although the physical association between Hsp90 and CRAF remains intact. We observe that over-expression of Hsp90 stimulates MAPK signaling by activating CRAF. The interaction between Hsp90 and CRAF is substantially increased under elevated level of cellular Hsp90 and in presence of either active Ras (RasV12) or EGF. Surprisingly, enhanced binding of Hsp90 to CRAF occurs prior to the Ras-CRAF association and facilitates actin recruitment to CRAF for efficient Ras-CRAF interaction, which is independent of Hsp90s ATPase activity. However, monomeric CRAF (CRAF R401H) shows abrogated interaction with both Hsp90 and actin, thereby affecting Hsp90-dependent CRAF activation. This finding suggests that stringent assemblage of Hsp90 keeps CRAF kinase equipped for participating in MAPK pathway. Thus, the role of Hsp90 in CRAF maturation and activation acts as a limiting factor to maintain the function of a strong client like CRAF kinase.Functional mining of transporters using synthetic selections
October 3rd, 2016 by Hans J Genee
Nature Chemical Biology 12, 1015 (2016). doi:10.1038/nchembio.2189
Authors: Hans J Genee, Anne P Bali, Søren D Petersen, Solvej Siedler, Mads T Bonde, Luisa S Gronenberg, Mette Kristensen, Scott J Harrison & Morten O A Sommer
Polyketide and nonribosomal peptide retro-biosynthesis and global gene cluster matching
October 3rd, 2016 by Chris A Dejong
Nature Chemical Biology 12, 1007 (2016). doi:10.1038/nchembio.2188
Authors: Chris A Dejong, Gregory M Chen, Haoxin Li, Chad W Johnston, Mclean R Edwards, Philip N Rees, Michael A Skinnider, Andrew L H Webster & Nathan A Magarvey
Enzymatic hydrolysis by transition-metal-dependent nucleophilic aromatic substitution
October 3rd, 2016 by Sibel Kalyoncu
Nature Chemical Biology 12, 1031 (2016). doi:10.1038/nchembio.2191
Authors: Sibel Kalyoncu, David P Heaner, Zohre Kurt, Casey M Bethel, Chiamaka U Ukachukwu, Srinivas Chakravarthy, Jim C Spain & Raquel L Lieberman
Cbr1 is a Dph3 reductase required for the tRNA wobble uridine modification
October 3rd, 2016 by Zhewang Lin
Nature Chemical Biology 12, 995 (2016). doi:10.1038/nchembio.2190
Authors: Zhewang Lin, Min Dong, Yugang Zhang, Eunyoung Alisa Lee & Hening Lin
Diphthamide and the tRNA wobble uridine modifications both require diphthamide biosynthesis 3 (Dph3) protein as an electron donor for the iron-sulfur clusters in their biosynthetic enzymes. Here, using a proteomic approach, we identified Saccharomyces cerevisiae cytochrome b5 reductase (Cbr1) as a NADH-dependent reductase for Dph3. The NADH- and Cbr1-dependent reduction of Dph3 may provide a regulatory linkage between cellular metabolic state and protein translation.
Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells
October 3rd, 2016 by Cecilia Lopez-Sambrooks
Nature Chemical Biology 12, 1023 (2016). doi:10.1038/nchembio.2194
Authors: Cecilia Lopez-Sambrooks, Shiteshu Shrimal, Carol Khodier, Daniel P Flaherty, Natalie Rinis, Jonathan C Charest, Ningguo Gao, Peng Zhao, Lance Wells, Timothy A Lewis, Mark A Lehrman, Reid Gilmore, Jennifer E Golden & Joseph N Contessa
The AAA+ FtsH Protease Degrades an ssrA-Tagged Model Protein in the Inner Membrane of Escherichia coli
September 30th, 2016 by Sanjay B. Hari and Robert T. Sauer
Roger Y. Tsien 1952–2016
September 26th, 2016 by Amy E Palmer
Nature Chemical Biology 12, 887 (2016). doi:10.1038/nchembio.2213
Authors: Amy E Palmer & Jin Zhang
Roger Tsien left us on August 24. His untimely passing has saddened and shocked the scientific community. Roger literally and figuratively brightened our world, illuminated the dark matter of biology, and forever changed our view of the interface of chemistry and biology.
Structural basis for precursor protein–directed ribosomal peptide macrocyclization
September 26th, 2016 by Kunhua Li
Nature Chemical Biology 12, 973 (2016). doi:10.1038/nchembio.2200
Authors: Kunhua Li, Heather L Condurso, Gengnan Li, Yousong Ding & Steven D Bruner
Thermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat
September 26th, 2016 by Isabelle Becher
Nature Chemical Biology 12, 908 (2016). doi:10.1038/nchembio.2185
Authors: Isabelle Becher, Thilo Werner, Carola Doce, Esther A Zaal, Ina Tögel, Crystal A Khan, Anne Rueger, Marcel Muelbaier, Elsa Salzer, Celia R Berkers, Paul F Fitzpatrick, Marcus Bantscheff & Mikhail M Savitski
We describe a two-dimensional thermal proteome profiling strategy that can be combined with an orthogonal chemoproteomics approach to enable comprehensive target profiling of the marketed histone deacetylase inhibitor panobinostat. The N-hydroxycinnamide moiety is identified as critical for potent and tetrahydrobiopterin-competitive inhibition of phenylalanine hydroxylase leading to increases in phenylalanine and decreases in tyrosine levels. These findings provide a rationale for adverse clinical observations and suggest repurposing of the drug for treatment of tyrosinemia.