
Researchers illuminate new structures of a critical amyloid protein Insights could advance new drugs to treat the progressive, fatal disease known as transthyretin amyloidosis.
January 29, 2025
LA JOLLA, CA The tiny protein known as transthyretin can cause big problems in the body when it misfolds after secretion. While healthy transthyretin moves hormones through blood and spinal fluid, misfolded versions of the protein form dangerous clumps in the heart and along nerves triggering a progressive and fatal disease known as transthyretin amyloidosis (ATTR). Up to a quarter of all men over the age of 80 have some degree of ATTR, which can cause shortness of breath, dizziness and tingling or loss of sensation in the extremities.
Now, Scripps Research scientists have uncovered new structures of transthyretin. Their findings, published in Nature Structural & Molecular Biology on January 22, 2025, show how the three-dimension asymmetry of the protein may contribute to its instability. This discovery could also contribute to the development of new drugs for ATTR.
We've unveiled a molecular complexity that has been hidden from researchers for decades, which enables us to design better medicines to stabilize transthyretin, says co-senior author Gabriel Lander, PhD, professor at Scripps Research.
The new structures reveal differences in two thyroid hormone binding sites previously thought to be identical, and help explain why a drug binding to one site changes the ability of drugs to bind the opposing site, adds Jeffery Kelly, PhD, the Lita Annenberg Hazen Professor of Chemistry at Scripps Research and a co-senior author of the study.
To determine the three-dimensional structure of small proteins such as transthyretin, researchers often turn to crystallography, in which proteins are forced into a large, repetitive crystal structure before being imaged. However, the structure of a crystallized protein doesn't always reflect the conformation of individual free-floating proteins in the body.
Another method, cryo-electron microscopy (cryo-EM), flash-freezes proteins to catch them in their more natural structures. However, these frozen proteins are then suspended in a liquid and small proteins like transthyretin tend to get stuck at the air-liquid boundary rather than remaining fully submerged. This affects both the proteins' structural stability and the ability to illuminate their detailed structure.
To overcome this challenge, Lander's group developed a thin graphene-coated grid to which transthyretin molecules could naturally adhere. Then, they rapidly plunged this grid into liquid ethane to freeze the sample. This process trapped the transthyretin molecules in place on the graphene surface and preserved their natural conformations to mimic how they would appear when moving through the body's blood or fluids.
We built on the 2019 work from the Yan lab at Princeton when making our grids. Getting the surface chemistry right is crucial for this type of study. With small proteins like transthyretin, creating a high-quality sample is just the beginning; analyzing the data is also part of the challenge, says Benjamin Basanta, PhD, a former research associate in the Lander Lab and first author of the new paper.
When the team tested the approach with transthyretin, they discovered that transthyretin forms asymmetric structures with two differently shaped binding pockets. Based on the more than 200 crystal structures that had been solved in the past, these binding sites had been assumed to be identical. The researchers showed that this variation was because the transthyretin complex was constantly wiggling between two different states like a molecular version of breathing, according to Lander. This asymmetry in the native structure of transthyretin also presents a hypothesis for how the process of dissociation and misfolding could occur then lead to the clumping of the protein and subsequent disease.
Attaching the ATTR drug tafamidis developed by the Kelly lab to one or both of the transthyretin binding sites, they then found, stabilized the molecule and minimized this movement.
Now, Lander and his colleagues aim to study how this structure and its stabilization relate to ATTR, and how drugs targeting transthyretin could treat the disease. They also say that their graphene grid method could be used to determine the structures of other small and unstable proteins including the amyloid-beta peptide that builds up in the brain in Alzheimer's disease.
The methodologies we've developed have opened new doors to avenues of treatment that could one day protect patients from not just TTR amyloidosis, but other amyloid diseases as well, says Lander.
In addition to Lander, Kelly, and Basanta, authors of the study, The conformational landscape of human transthyretin revealed by cryo-EM, are Karina Nugroho, Nicholas L. Yan, Gabriel M. Kline, Evan T. Powers, Felix J. Tsai, Mengyu Wu, Althea Hansel-Harris, Jason S. Chen, and Stefano Forli of Scripps Research.
This work was supported by the National Institutes of Health (GM142196, AG067594, DK046335) and a Postdoctoral Fellowship from the George E. Hewitt Foundation for Medical Research.
Chemistry Molecular and Cellular Biology Lander, Gabriel Kelly, Jeffery
Most recent headlines
04/09/2025
Monumental Sports & Entertainment (MSE), in collaboration with Dalet, has been a...
21/04/2025
By Lucy Spicer
One of the most exciting things about the Sundance Film Festival is having a front-row seat for the bright future of independent filmmaking. Whi...
21/04/2025
Advertising investment up 9% YoY for travel and accommodationSydney - April 16, 2025 - Nielsen Ad Intel data shows that travel and accommodation has grown stron...
21/04/2025
NEW YORK Samsung Ads, the advanced advertising division of Samsung Electronics, has announced the availability of its Optimal Reach solution for advertisers acr...
21/04/2025
DENVER, Colo. A new survey highlights just how important streaming has become in...
21/04/2025
The strength of kindness: Collaborative effort helps Special Olympics World Wint...
21/04/2025
Nashville Juggles A Cornucopia Of Sports With Its Star on the Rise NFL, NHL, MLS, MLB AAA, NASCAR want a place in Music City By Dan Daley, Audio Editor
Monda...
21/04/2025
SVG Sit-Down: Telstra Broadcast Services CEO Karen Clark on the Challenge of Liv...
21/04/2025
Award Winning Producer/Director Don Mischer Dead at 85 By Ken Kerschbaumer, Editorial Director
Monday, April 21, 2025 - 12:30 pm
Print This Story | Subscr...
21/04/2025
The Fox Sports Way: How AR Graphics, XR Tech, and LED Displays Have Become Cente...
21/04/2025
Fox Corporation Executives to Discuss Third Quarter Fiscal 2025 Financial Result...
19/04/2025
SDVI, the leading platform provider for cloud-native media supply chains, today announced that the company earned multiple awards at the 2025 NAB Show, with two...
19/04/2025
Ateliere Creative Technologies, a leading GenAI media software solutions company, today announced that Dan Goman has stepped down as CEO and David Bortis, Ateli...
19/04/2025
As Director of Media and Aerial Production at Terrible Herbst Motorsports, Bryan Moore is setting new standards in off-road racing media coverage thanks to his ...
19/04/2025
A next-generation collaboration device that redefines connectivity for meeting environments
Lightware, an industry-leading manufacturer of signal management so...
19/04/2025
Calrec is today announcing that its True Control 2.0 is a Remote Production winner in the 2025 NAB Show Product of the Year Awards. This official awards program...
19/04/2025
Appear, a global leader in live production technology, proudly announces it has been recognised alongside NBCUniversal with the prestigious NAB Show Delivery Pr...
19/04/2025
Deity Microphones, a leader in innovative audio equipment, is proud to announce the expected release of our Ultra-Wide Band IFB to the market. The THEOS DIFB wi...
19/04/2025
A world renowned broadcaster and long-standing LiveU customer has successfully completed a series of live connectivity tests using LiveU's revolutionary, aw...
19/04/2025
BitFire (bitfire.tv), a longtime leader in live video transport, today announced dual NAB Show award wins at the 2025 NAB Show in Las Vegas. The company's M...
19/04/2025
BitFire (bitfire.tv), a longtime leader in live video transport, today announced three major award wins at the 2025 NAB Show, April 5-9, in Las Vegas. The compa...
19/04/2025
AI video discovery company Moments Lab and Satisfaction Group, a leading independent unscripted television production company, are proud to announce a unique st...
19/04/2025
As the media industry navigates the triple challenge of AI-driven production, distributed teams, and skyrocketing content demand, DigitalGlue s creative.space h...
19/04/2025
Network technology startup Miri Technologies Inc. capped off its tremendously successful NAB Show debut by winning two prestigious industry awards for its cutti...
19/04/2025
CINCINNATI Scripp's Nuvyyo USA has concluded a deal with Warner Bros. Discovery to bring 45 FAST channels to Nuvyyo's Tablo TV device....
19/04/2025
In a ruling that could have broader implications on the legality of regulatory agencies levying fines through administrative proceedings, the 5th U.S. Circuit C...
19/04/2025
WASHINGTON Federal Communications Commission chair Brendan Carr has blasted Comcast over MSNBC's coverage of the deportation of Kilmar Abrego Garcia in a so...
19/04/2025
Berklee NYC and NYC Media Launch Season 3 of Inside Power Station @BerkleeNYC This season features faculty member Arun Pandian as the new host and interviews ...
18/04/2025
Director Andrew Ahn, alongside actors Youn Yuh-jung and Joan Chen, takes a photo of the audience after the premiere of his film The Wedding Banquet at Eccles ...
18/04/2025
In a ruling that could have a major impact on the digital advertising market, a federal judge has ruled that Google has monopolized some types of advertising te...
18/04/2025
Broadcast and cable TV news outlets saw strong social media growth in March, according to new data from the social video analytics company Tubular Labs ....
18/04/2025
Berklee Student Yukai Yang Named 2025 Yamaha Young Performing Artist The drummer secured a spot among the elite winners in this years competition.
By
Maddie...
18/04/2025
Boston Conservatory Alums Bring Real Women Have Curves to Broadway The Latin American immigrant community takes center stage in a new musical featuring Tatian...
18/04/2025
WASHINGTON The FCC's call for public comments and suggestions on outdated regulations that it should be eliminated, has prompted a slew of fillings from bro...
18/04/2025
In a ruling that could have a major impact on the digital advertising market, a federal judge has ruled that Google has monopolized some types of advertising te...
18/04/2025
PEARL RIVER, N.Y. Global media solutions company Active Media Services (AMS) has formed a new relationship with VideoAmp, a measurement company for linear TV, c...
18/04/2025
Netflix reported generally positive results for first-quarter 2025, with revenue up 13% year-over-year to $10.543 billion and operating income growing by 27% to...
18/04/2025
NHL Playoffs 2025: TNT Sports Hits the Road for Onsite Productions With Mobile U...
18/04/2025
EVSs S bastien Verlaine on U.S. Expansion, Next-Generation Products Beyond replay, offerings also target asset management and media infrastructure By Ken Kersc...
18/04/2025
ESPN Unleashes 4DREPLAY as NCAA Women's Gymnastics Championships Hit ABC Men's championships to follow Saturday night on ESPN2 By Brandon Costa, Direct...
18/04/2025
Visualizing Victory: The Latest in AR, XR, and Virtual Production in Live Sports This panel discussion featured leaders from ESPN, CBS Sports, Warner Bros. Disc...
18/04/2025
NHL Playoffs 2025: With 16 Games in First Six Days, ESPN Deploys Variety of Remo...
17/04/2025
Emilie Blichfeldt attends the 2025 Sundance Film Festival premiere of The Ugly ...
17/04/2025
R-GPS gives warfighters a decisive battlefield advantage by punching through adv...
17/04/2025
This year's NAB Show in Las Vegas marked a noticeable shift in the priorities of media and broadcast organisations. Gone are the days of chasing flashy, or ...
17/04/2025
class=attachment-thumbnail size-thumbnail f-align-center alt= decoding=async data-lazy-srcset=https://www.antonbauer.com/wp-content/uploads/2024/12/Amy-Daniel-1...
17/04/2025
SAN JOSE, Calif. Roku and Adobe have announced that they are collaborating on a real time data platform made possible by a a new integration of the Roku Data C...
17/04/2025
NEW YORK Internet advertising revenues demonstrated strong growth in 2024, increasing 14.9% year-over-year to $258.6 billion, according to the IAB Internet Adv...
17/04/2025
SDVI Earns Both Product and Project of the Year Awards at 2025 NAB Show
Brie Clayton April 17, 2025
0 Comments
Left to right, Geoff Stedman, CMO, SDVI...
17/04/2025
Singapore Polytechnic Readies Aspiring AV Professionals for Live IP Productions ...