Press Releases

Snake-like proteins can wrangle DNA

Rice study reveals details about how coiled coils may coil again to direct chromosome process


0113_BRAIDS-1-RN This illustration by Rice University scientists demonstrates that cohesin exists as an ensemble of braided structures (middle). Cohesin is a member of a family of proteins that have an important role in DNA organization, but little is known about the mechanism of DNA operation. Braiding of coiled coil regions was achieved in Rice’s computational models using both the initial ring-shaped complex (right) or by applying torque to separated protein members (left). Protein members are shown in blue and red. (Illustration by Dana Krepel)
By riceuniversity | January 6, 2020

HOUSTON – (Jan. 2, 2020) – It turns out the coiled snakes often used to symbolize medical knowledge are more than apt. They also mimic a key to life itself.

Members of Rice’s Center for Theoretical Biological Physics (CTBP) are taking a deep dive into the dynamics of essential proteins that help DNA fold into its compact, functional form in chromosomes. They found a key protein’s “coiled coils” also braid around each other and writhe like snakes as they form bigger loops in the DNA.

The loops, in turn, bring together sites on DNA that regulate the transcription of genetic messages. While the loops and their functions are becoming better understood, until now nobody has been able to take a close look at the condensin and cohesin proteins that wrangle the DNA into shape.

The Rice team led by physicists José Onuchic and Peter Wolynes and postdoctoral fellow Dana Krepel report in the Proceedings of the National Academy of Sciences that structural maintenance of chromosomes (SMC) proteins may actively manage DNA through a novel mechanism.

They found these proteins have ring-shaped lassos that consist of two 35-nanometer long protein coiled coils. These terminate on one end in a pair of “head unit” motors that bind to DNA coils, and on the other in “hinges” thought to open and close to entrap the strands.

The lab’s simulations showed these coiled coils are anything but limp lariats.

“We already knew the coiled coils have some sort of structural importance, but what we saw is that these long coils are quite active,” Krepel said. “We’re still investigating to what extent, but as we ran the simulations, we saw that the coils want to come together, kind of like headphones that get all twisted when you put them in your bag. We saw the twist right away.”

“Braiding is the word we use,” Wolynes added. “People thought the coiled coils were simply hanging out, but they didn’t think they’d coil again on top of each other in an organized fashion.

“One of the key ideas of DNA physics is that DNA operates by changing its degree of coiling and its topology,” he said. “Well, braiding is a topological feature. We think we see that the topology of the protein can interact with the topology of the DNA much as threads entwine with each other on a spinning wheel.”

Krepel noted the SMC proteins are positively charged, and DNA is negatively charged. “We’re looking at how these positive and negative charges potentially play together,” she said.

“It seems clear the coils would almost certainly braid themselves around the DNA using these charge patterns,” Wolynes said.
The project represents one of the largest challenges yet for the group’s modeling techniques, which in this case combined direct coupling analysis (DCA) of the co-evolution of related protein sequences and the atomic forces within the proteins that determine their form and function.

To complete the structure in which there were fewer evolutionary clues, the group used the AWSEM algorithm developed by Wolynes and colleagues to determine complete folded, functional structures from a coarse subset of atomic forces within a protein.

For this study, the team looked at condensin and cohesin structures with between 1,100 to 1,300 residues. “These are huge compared to proteins we have previously studied,” Wolynes said.

The size made it necessary to expand the tool set, Onuchic said. “An initial paper developed these tools but just for condensin in bacteria,” he said. “Utilizing the same approach of DCA combined with structure-based simulations, we are now investigating condensin and cohesin as they appear in humans.

“Using this method, we are able to predict the structures, but to understand the details of their dynamics requires real force fields,” Onuchic said. “So starting from the initially predicted structures, we ran AWSEM simulations. These simulations revealed the braiding.”

The models further suggested that the ATPase motors that bind DNA can twirl the braids.

“We’re still guessing at the details, but we think when the two motors are both twisting to extrude DNA into loops, one untwisting and the other uptwisting, the lassos could transfer twisting of the coils into twisting around the DNA,” Wolynes said. “The coils aren’t just passively hanging there. They’re much more involved in the process than we thought.”

The next step, he said, will be to test an even larger system with two strands of DNA, a more realistic representation, to see if the twisting action holds true. That effort will be part of a larger one at CTBP to extend its theories on protein folding to the much bigger problem of chromosome dynamics. The researchers pointed out this will be one of the main goals of the center’s future work.

“This molecule and how it forms loops in DNA is a big part of many projects we have going on in chromosomes,” Wolynes said. “There are quite a few diseases that arise from chromosome disorganization, and we want to have a better understanding of the mechanism of how chromosomes form.”

Rice researchers Aram Davtyan and Nicholas Schafer are co-authors of the paper. Wolynes is the D.R. Bullard-Welch Foundation Professor of Science, a professor of chemistry, of biosciences, of physics and astronomy and of materials science and nanoengineering at Rice. Onuchic is the Harry C. and Olga K. Wiess Chair of Physics, a professor of physics and astronomy, of

chemistry and of biosciences. Both are co-directors of the National Science Foundation-funded CTBP.
The National Science Foundation, the Welch Foundation and the Council for Higher Education of Israel supported the research.

 

Read the abstract at https://www.pnas.org/content/early/2019/12/26/1917750117




Social Posts

profile_image

MD Anderson Cancer Center

@MDAndersonNews

@Marissa_lara14 We're thinking of you, Marissa.

25 mins ago
profile_image

BCMHouston

@bcmhouston

RT @jmills1955: Annual Surgical Jeopardy ⁦@BCM_Surgery⁩ Residents vs Faculty. The Faculty have never won! ⁦@DrRosengart⁩ ⁦@kmattox1⁩ ⁦@drml…

27 mins ago
profile_image

Veterans Affairs

@DeptVetAffairs

Veterans ask, VA answers: Questions on electronic health record modernization. https://t.co/IkeHFZV0zn via #VAntagePoint

48 mins ago
profile_image

Veterans Affairs

@DeptVetAffairs

103-year-old WWII Veteran finally gets the recognition he deserves https://t.co/shJIdq9Ju9 via @CBSEveningNews

11 hours ago
profile_image

MD Anderson Cancer Center

@MDAndersonNews

Watch to learn how we’re enhancing the ability of patients’ own T cells to fight cancer. #endcancer https://t.co/sFMz5eExco

11 hours ago
profile_image

MD Anderson Cancer Center

@MDAndersonNews

Today’s rising #livercancer rates have been driven by non-alcoholic fatty liver disease, which is linked to obesity.But our experts are working with @ScrippsHealth to study an #immunotherapy combination to treat liver cancer and save lives: https://t.co/uwAhLH51uk #endcancer

12 hours ago
profile_image

Veterans Affairs

@DeptVetAffairs

College of Charleston looks to send dozens of Valentine’s Day cards to Veterans https://t.co/fFqeaN3T7o via @ABCNews4

13 hours ago
profile_image

BCMHouston

@bcmhouston

Dorit Donoviel, Ph.D., discusses taking risks in science and what the Translational Research Institute for Space Health is doing to help people in space with @InnoMapHou. https://t.co/wbML42L9Wb #space #spacemedicine

13 hours ago
profile_image

BCMHouston

@bcmhouston

RT @bcm_ocd: Check out this chapter by our researchers in new book Exposure Therapy for Children with Anxiety and OCD. "Efficacy of exposur…

15 hours ago
profile_image

University of Houston

@UHouston

RT @UH_Pharmacy: Breaking: With 100% chance of rain for Wed, Jan. 22, the "Shine A Light on Mental Health" fair from noon to 2 pm has been…

16 hours ago
profile_image

Texas Children's

@TexasChildrens

For the second consecutive year, Transplant Services at @TexasChildrens was named the top pediatric transplant center in the US, performing a remarkable 106 solid organ transplants in 2019. Learn more: https://t.co/iR6xO02dTC https://t.co/aOPfISdYhs

17 hours ago
profile_image

University of Houston

@UHouston

Which Shasta are YOU? Check out our new Instagram face effects, available now! https://t.co/POQlqNnN3W

18 hours ago
profile_image

Texas Children's

@TexasChildrens

Join us this Saturday, January 25 for All About HER! (Health, Emotions & Relationships) at @TexasChildrens The Woodlands! To register, visit: https://t.co/7dqWlmWZOg https://t.co/J84AYU8aZW

18 hours ago
profile_image

Texas Children's

@TexasChildrens

Feeling the love on #NationalHugDay 🤗 #AstrosCaravan @OrbitAstros @astros https://t.co/fqD7iWP7AH

19 hours ago
profile_image

TexasHeartInstitute

@Texas_Heart

Belly fat, more than excess weight, may be a factor in the risk for multiple heart attacks, according to a new study. Tackle that belly fat with a heart-healthy diet and exercise. https://t.co/8f3YKQOlPJ via @CNN https://t.co/bDi6EYVVHZ

20 hours ago