A new study that uncovers a pathway critical for proper embryological development in zebra fish may also reveal a parallel mechanism that drives wiring of the vertebrate brain. The research, published by Cell Press in the April 23 issue of the journal Molecular Cell provides intriguing insight into the complex signaling mechanisms of fragile-X proteins.
Fragile-X syndrome (FXS), the most common cause of inherited mental retardation, arises from mutations in the fragile X mental retardation (FMR) gene. This FMR1 protein, and the closely related FXR1 protein, both have multiple regions that bind mRNAs (molecules that are critical for the synthesis of new proteins). One such region is a conserved KH2 domain that has long been suspected to also bind proteins and, when mutated, inactivates the entire FMR1 protein.
"We know that in the brain, fragile-X proteins recruit and control mRNA translation at sites where local protein synthesis is needed to organize synapses," explains senior study author, Dr. Ed Manser from the Agency for Science, Technology and Research in Singapore. "But how the fragile-X protein complex is put together, and whether partners for the KH2 domain exist have never been clearly established."
Manser and his colleagues looked for proteins that might bind to the brain-enriched p21-activated kinase (PAK). PAK, which was first discovered by Dr. Manser's research group in Singapore, also plays a key role in the development of synapses in the brain. "We found that FXR1 protein, which is present in all cells, binds PAK1 only when the kinase is in an "open" active conformation. PAK1 binds to the brain FMR1 protein via the KH2 domain in the same way," explains Dr. Manser. "Our most exciting finding was that the KH2 mutant could not bind PAK at all."
The researchers went on to show that PAK phosphorylated FXR1 elsewhere (at a specific site called Ser420) and that this modification was needed to properly make muscle in their test organism, the zebra fish. The authors suggest that the same kind of protein-mRNA complexes that operate in newly formed muscles may also be required for the development of synapses.
"We provided compelling evidence for an interaction between PAK1 and FXR1 via a well-defined protein-protein interface, and showed that phosphorylation of FXR1was critical to get the protein working," concludes Dr. Manser. "In the future we plan to further investigate the interplay between PAK1 and associated proteins in synapses. In fact, we have recently discovered and purified from brain a completely new protein which looks like it may provide another important piece to the fragile X puzzle."
The researchers include Evonne Say, sGSK Group at IMCB, Neuroscience Research Partnership, Singapore; Hwee-Goon Tay, Astar Institute of Medical Biology (IMB), Singapore; Zhuo-shen Zhao, sGSK Group at IMCB, Neuroscience Research Partnership, Singapore; Yohendran Baskaran, sGSK Group at IMCB, Neuroscience Research Partnership, Singapore; Rong Li, Experimental Therapeutics Centre (ETC), Singapore; Louis Lim, UCL Institute of Neurology, London, UK; and Ed Manser, sGSK Group at IMCB, Neuroscience Research Partnership, Singapore, Astar Institute of Medical Biology (IMB), Singapore.
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