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Howard Hughes Medical Institute scientists have determined thethree-dimensional structure of two proteins that help keep thebody's clocks in sync. The proteins, CLOCK and BMAL1, bind to eachother to regulate the activity of thousands of genes whoseexpression fluctuates throughout the course of a day. Knowing thestructure of the CLOCK:BMAL1 complex will help researchersunderstand the intricacies of how this regulation is carried outand how mutations in each protein lead the biological clock to goawry. Every 24 hours, millions of 'clocks' inside of our cells reset,helping to tune sleep patterns, blood pressure, and metabolism.When CLOCK and BMAL1 bind to one another inside cells, theyinitiate the first genetic events that coordinate this 24-hourcycle. "CLOCK and BMAL1 are really the batteries of the biologicalclock," says HHMI investigator Joseph S. Takahashi of theUniversity of Texas Southwestern Medical Center, whose findings onthe CLOCK:BMAL1 structure are published in the online version ofthe journal Science . "They are the key activators of the whole genomic regulationsystem." The Clock gene was the first mammalian gene found to contribute tothe body's circadian rhythms. Takahashi's team published theinitial data on the Clock gene in a series of papers spanning 1994to 1997. Since then, they've uncovered hundreds to thousands ofgenes under the control of CLOCK that fluctuate in sync with thebiological clock in mammals. "What's amazing is that we've now found out that almost every cellin your body has a clock," says Takahashi. "Over the past fiveyears, the role of those clocks in peripheral tissues has reallycome to the forefront." Researchers studying circadian rhythms have used biochemistry andgenetics to piece together rough outlines of how each circadianprotein interacts with CLOCK. But until now, they'd never been ableto visualize the detailed molecular structure of the CLOCK protein.Seeing such a structure would allow them to visualize how differentproteins can bind to CLOCK at the same time, or compete for bindingspots, and how mutations known to alter circadian rhythms affectthis binding. Takahashi notes that CLOCK and BMAL1 are part of a large family ofproteins, known as bHLH-PAS proteins (a name that refers to both tothe shape of the protein and some better known members of thefamily), involved in functions ranging from responding toenvironmental contaminants and low-oxygen levels to the creation ofnew nerve cells. "It's not just CLOCK for which we didn't have astructure," says Takahashi. "This class of protein had never beensolved at the crystallographic level before." Takahashi explained that researchers had struggled to generatecircadian proteins in the crystalline form necessary to determinestructure using x-ray crystallography, but by experimenting withdifferent conditions, his team was able to purify CLOCK bound toBMAL1. Rather than use the full-length version of each protein,they created a version consisting of only the pieces known tointeract with each other. Having shorter proteins made the processeasier. The scientists discovered that CLOCK and BMAL1, when together, areclosely intertwined. CLOCK has a groove in the center of itsinterface that's key to binding. A single amino acid of BMAL1 fitsperfectly into the groove. Other proteins that bind to CLOCK likelytake advantage of the same spot. Future research will look into theexact positions in which other circadian rhythm proteins bind tothe complex, and how mutations to each protein affect thestructure. "Since these are truncated versions of the proteins, what we'dreally like to do is to go on to get full-length structures," saysTakahashi. They also want to understand how the Cryptochrome andPeriod proteins that turn off the activity of CLOCK bind to theCLOCK:BMAL1 complex. But that will take time. Additional References Citations. I am an expert from smd-ledtube.com, while we provides the quality product, such as T5 LED Tube , LED Landscaping Lights Manufacturer, LED Flat Panel Lights,and more.
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