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'Pump' mechanism splits DNA for copying by RNA

High-resolution images offer new insight into the structure of the replisome, a molecular protein machine that unwinds, splits, and copies double-stranded DNA.


New close-up images of the proteins that copy DNA inside the nucleus of a cell from the U.S. Department of Energy's Brookhaven National Laboratory, Stony Brook University, Rockefeller University, and the University of Texas, reveal a brand new mechanism for how this molecular machinery works.

Scientists studied yeast proteins, which share many features with human proteins, to offer new insight into how DNA replication can go wrong.


"DNA replication is a major source of errors that can lead to cancer. Throughout the entire genome, all 46 chromosomes are replicated every few hours in dividing cells. Studying the details of how this process works helps us understand how errors occur."

Huilin Li PhD, Biologist, joint appointment at Brookhaven Lab and Stony Brook University and the lead author on a paper.


The work appears in the journal Nature Structural and Molecular Biology and builds on previous work by Li, and others, that produced the first-ever images of a complete DNA-copying protein complex, called the replisome.

That study revealed a surprise about the location of the DNA-copying enzymes — DNA polymerases.

This new study zooms in on the atomic-level details of the "helicase" — those enzymes that encircle and split the DNA double helix — which must separate the DNA in order to copy the two strands of its "twisted ladder" in order for cells to multiply and build tissues.

The scientists produced high-resolution images of the helicase using cryo-electron microscopy (cryo-EM). One advantage of this method is that proteins can be studied wet, which is how they exist and function in our cells. Huilin Li PhD: "You don't want to produce crystals that would lock proteins into one position. You want to be able to see how the molecule moves to understand its function."


The helicase is a molecular "machine" made of 11 proteins that must flex in order to work.


Using computer software, images revealed that the helicase has two distinct shapes — one with its parts stacked compactly, the other where part of the structure is tilted relative to its "fixed" base.

This atomic-level view allowed scientists to map the location of each individual amino acid in the helicase complex to each of the two shapes. With their existing biochemical knowledge, the scientists came up with an idea of how the helicase works.


"One part [of the helicase] binds and releases energy from a molecule called ATP. It converts the chemical energy into mechanical force that changes the shape of the helicase."

Huilin Li PhD


After kicking out the used up ATP, the helicase complex goes back to its original shape so that a new ATP molecule can be sucked in, starting the process all over again. Li suggests that each rocking motion nudges the DNA strands apart and moves the helicase linearly along the double helix.


"It looks and operates similar to an old style pumpjack oil rig, with one part of the protein complex being a stable platform, and the other part rocking back and forth."

Huilin Li PhD


It was thought that in more primitive organisms, such as bacteria, the entire helicase complex rotated around the DNA. But there is biochemical evidence supporting the idea of a linear motion, including the fact that the helicase functions even when some components are turned off by mutation.
  Helicase

"We acknowledge this proposal may be controversial as it is not really proven at this point, but the structure gives an indication of how this [helicase] protein complex works and we are trying to make sense of it."

Huilin Li PhD


Abstract
The CMG helicase is composed of Cdc45, Mcm2–7 and GINS. Here we report the structure of the Saccharomyces cerevisiae CMG, determined by cryo-EM at a resolution of 3.7–4.8 Å. The structure reveals that GINS and Cdc45 scaffold the N tier of the helicase while enabling motion of the AAA+ C tier. CMG exists in two alternating conformations, compact and extended, thus suggesting that the helicase moves like an inchworm. The N-terminal regions of Mcm2–7, braced by Cdc45–GINS, form a rigid platform upon which the AAA+ C domains make longitudinal motions, nodding up and down like an oil-rig pumpjack attached to a stable platform. The Mcm ring is remodeled in CMG relative to the inactive Mcm2–7 double hexamer. The Mcm5 winged-helix domain is inserted into the central channel, thus blocking entry of double-stranded DNA and supporting a steric-exclusion DNA-unwinding model.

The study was funded by the U.S. National Institutes of Health and the Howard Hughes Medical Institute (HHMI), with additional support from the Brookhaven Lab Biology Department. High-resolution cryo-EM data were collected at HHMI and the University of Texas Health Science Center.

Brookhaven National Laboratory is supported by the Office of Science of the U.S. Department of Energy. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information, please visit science.energy.gov.

One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation for the State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit applied science and technology organization.

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Feb 23, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



[LEFT] Old "textbook" idea. [RIGHT] New concept revealed by electron micrograph imaging.
Old: two polymerases (GREEN) at bottom or back of helicase (TAN), copy DNA side by side.
New: one polymerase is located at the bottom of the helicase, while a second flexs and tilts.
Image Credit: Brookhaven Lab and Stony Brook University, NATURE


 

 


 

Phospholid by Wikipedia