Deciphering the Mysteries of Unstructured Proteins
UT Southwestern ❘ Discovery@UTSW 2026 ❘ P4–5 McKnight Profile
Discoveries by Steven McKnight, Ph.D., have revealed the active role of shapeless protein regions known as low-complexity domains in gene regulation.
Proteins are made of a combination of 20 amino acids, the sequence of which determines how they fold into precise shapes and sustain their functions throughout the body. However, approximately 20% of proteins defy this paradigm, containing extended regions that lack sufficient chemical interactions to snap into a well-defined structure.
Over the last two decades, Steven McKnight, Ph.D., Professor of Biochemistry, has studied these protein regions, called low-complexity domains (LCDs). His work has helped to reveal how these flexible proteins contribute to an incredible number of dynamic cellular processes and neurologic and neurodegenerative disease.
Award-Winning Research
In 2025, Dr. McKnight received the prestigious Albert Lasker Basic Medical Research Award, often referred to as “America’s Nobel,” in recognition of furthering our understanding of LCDs. He shared this award with Dirk Görlich, Ph.D., a German biochemist who is director of the Max Planck Institute for Multidisciplinary Sciences.
Dr. McKnight’s recognition marks the second consecutive year and fifth time that a UT Southwestern scientist has earned a Lasker Award.
“This honor illustrates the level of fundamental research that takes place at UT Southwestern,” says W. P. Andrew Lee, M.D., Executive Vice President for Academic Affairs, Provost, and Dean of UT Southwestern Medical School. “Dr. McKnight’s work provides insight into how cells organize proteins for critical functions and what goes awry in some neurologic and neurodegenerative diseases. That is crucial information to develop new and better treatments.”
For Dr. McKnight, science is the ultimate adventure. “Pursuing the unknown and trying to figure out something that’s otherwise complicated and obscure, that’s really the fun of it for me,” says Dr. McKnight, who holds the Distinguished Chair in Basic Biomedical Research and is a member of the Harold C. Simmons Comprehensive Cancer Center.
His findings on LCDs are a testament to his curiosity-driven research approach.
“Steve is a passionate, inquisitive person who has pursued a mechanistic understanding of the basis for key problems in cellular biology throughout his career. Each new answer leads him to another question,” says Margaret Phillips, Ph.D., Professor and Chair of Biochemistry. “The discoveries he’s made pursuing those questions over the last three decades have had a tremendous impact on the field of biochemistry as a whole.”
An ‘Aha’ Moment
Born and raised in El Paso, Texas, Dr. McKnight earned a bachelor’s degree in biology from the University of Texas at Austin and a Ph.D. in biology from the University of Virginia. He then went to the Carnegie Institution of Washington for postdoctoral training and stayed as a staff member. He joined UTSW in 1995, serving as Chair of the Department of Biochemistry from 1996 to 2016.
In the 1980s, Dr. McKnight studied transcription factors, proteins that regulate gene expression by binding to specific DNA sequences and acting as switches to turn genes on and off. He and his colleagues found that certain transcription factors that have LCDs require the unstructured sections to work properly. However, since “structure equals function” had long been a paradigm in biology, the team couldn’t figure out why these strange, shapeless portions were so important.
By the 1990s, Dr. McKnight had moved on to other questions about gene regulation, leaving LCDs behind. But in 2010, Dr. McKnight began experimenting with a chemical – an isoxazole compound – that prompted embryonic stem cells to differentiate into beating heart cells. To better understand why, McKnight and his colleagues added this compound to cell extracts to see what proteins it might be interacting with to incite the change.
Expecting to find just one, or at most a handful of interacting proteins, the researchers were astonished to see that the isoxazole compound bound to hundreds of different proteins, a result that usually suggests the experiment failed, Dr. McKnight explains. However, the determined researchers continued to investigate what all of these proteins could have in common. Dr. McKnight found that all of the proteins contained LCDs and the proteins were suddenly snapped back into his focus.
Further studies showed that the isoxazole compound made LCD-containing proteins behave strangely – creating small gelatin-like balls that would form out of the mixture.
“In front of our eyes, a gel formed, and I'd never seen that before,” says Dr. McKnight. “That was the ‘aha’ moment.”
These balls of gel-like material were formed from LCDs’ fleeting chemical bonds with themselves and other parts of proteins.
Research over the next several years showed that these temporary interactions encourage dynamic protein organization that’s necessary for a host of critical cellular functions, such as gene regulation, cell signaling, and stress responses. Dr. McKnight’s research has also shown that mutations in LCDs could be responsible for several different neurodegenerative diseases, such as Charcot-Marie-Tooth disease, frontotemporal dementia, and Paget’s disease.
Important Questions and High Expectations
In another line of research, a partnership with David Russell, Ph.D., Professor Emeritus and former Vice Provost and Dean of Basic Research, revealed the HIF-2α transcription factor and identified its role in adapting cells and tissues to conditions of oxygen starvation. The discovery led to the development of a chemical inhibitor of HIF-2α called belzutifan, which was approved by the U.S. Food & Drug Administration in 2021 to treat kidney cancer.
Dr. McKnight’s research has also been honored with the Robert A. Welch Award in Chemistry (2020), the Wiley Prize in Biomedical Sciences (2014), the National Institutes of Health Director’s Pioneer Award (2004), the Monsanto Award from the National Academy of Sciences (1991), and the Eli Lilly Award from the American Society for Microbiology (1989). He is a former Howard Hughes Medical Institute Investigator and a member of the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences.
“The way that science is performed at UT Southwestern is simply wonderful,” Dr. McKnight says. “We’re asked to probe challenging and important questions, and the expectations are very high.”