Award

Wangeline honored for work on protein quality control

She won the JBC/Tabor Young Investigator Award
Isha Dey
March 1, 2019

Margaret Wangeline and her PI Randolph Hampton coined the term “mallostery” for an allosteric misfolding of the rate-limiting enzyme for cholesterol biosynthesis. Chemistry and its application in biology have always fascinated Margaret Wangeline. This interest drove her to explore how cells “manage, fix, and destroy misfolded proteins,” she said.

Wangeline grew up in northern California and then moved east for an undergraduate program in the department of chemical engineering at the Massachusetts Institute of Technology. There she studied how cells sense and repair damaged DNA, as well as metabolic responses to stress such as trauma.

Margaret Wangeline

Intrigued by the general idea of DNA and hence protein quality control and its implications in the human body, Wangeline headed back to the West Coast to pursue a Ph.D. in Randolph Y. Hampton’s lab in the department of biological sciences at the University of California, San Diego. There, she deduced that the misfolding and degradation of HMG-CoA reductase, or HMGR, the rate-limiting enzyme for cholesterol biosynthesis, is controlled selectively by a compound called geranylgeranyl pyrophosphate, or GGPP, in an allosteric manner (meaning the compound binds to HMGR at a site other than its catalytically active site). She and Hampton termed this allosteric misfolding “mallostery.” Their findings were published in the Journal of Biological Chemistry.

Besides troubleshooting experiments and writing manuscripts, Wangeline enjoys teaching, and in 2013 she won a UCSD excellence in teaching award. Her other interests include writing fiction stories, cooking and hiking. She also participates in science outreach activities through the university and elsewhere.

Wangeline plans to continue her research as a postdoc to understand better how protein quality control affects metabolism and how this applies to neurodegenerative diseases in general.

Looking back, she said her biggest lesson as a graduate student was to “not get discouraged from trying new things, and to step out of my comfort zone.”

The misfolding that makes “mallostery”

Protein quality control, including the selective degradation of misfolded proteins and getting rid of toxic products, is essential to maintain normal functioning of a cell. In mammalian systems, the most prominent pathway for protein quality control is endoplasmic reticulum-associated degradation, or ERAD.

Physiologically important enzymes often undergo controlled degradation as a feedback mechanism for their function. One such enzyme is the HMG-CoA reductase, or HMGR, the rate-limiting enzyme of the sterol synthesis pathway. On receiving signals to stop sterol production, HMGR is degraded by the ERAD pathway.

In Hampton’s lab, Wangeline and colleagues looked at the selectivity of the ERAD pathway to design strategies for controlling protein levels in the system. They discovered that a compound called GGPP selectively interacted with Hmg2, a yeast isozyme for HMGR, and directed Hmg2 for degradation. However, two different structural analogs of GGPP failed to do so.

Using a combination of biochemical methods, the lab deduced that GGPP bound to an allosteric site and caused changes in the folding state of Hmg2 to mark it for ERAD. The effects of GGPP could be reversed by chemical chaperones (analogous to proteins that assist in the correct folding of other proteins).

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition monthly.

Learn more
Isha Dey

Isha Dey is a scientist at Thermo Fisher Scientific.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in People

People highlights or most popular articles

Cedeño–Rosario and Kaweesa win research award
Member News

Cedeño–Rosario and Kaweesa win research award

Sept. 8, 2025

The award honors outstanding early-career scientists studying cancer, infectious disease and basic science.

ASBMB names 2026 award winners
Award

ASBMB names 2026 award winners

Sept. 5, 2025

Check out their lectures at the annual meeting in March in the Washington, D.C., metro area.

Peer through a window to the future of science
Annual Meeting

Peer through a window to the future of science

Sept. 3, 2025

Aaron Hoskins of the University of Wisconsin–Madison and Sandra Gabelli of Merck, co-chairs of the 2026 ASBMB annual meeting, to be held March 7–10, explain how this gathering will inspire new ideas and drive progress in molecular life sciences.

Castiglione and Ingolia win Keck Foundation grants
Member News

Castiglione and Ingolia win Keck Foundation grants

Sept. 1, 2025

They will receive at least $1 million of funding to study the biological mechanisms that underly birds' longevity and sequence–function relationships of intrinsically disordered proteins.

How undergrad research catalyzes scientific careers
Essay

How undergrad research catalyzes scientific careers

Aug. 27, 2025

Undergraduate research doesn’t just teach lab skills, it transforms scientists. For Antonio Rivera and Julissa Cruz–Bautista, joining a lab became a turning point, fostering critical thinking, persistence and research identity.

Simcox and Gisriel receive mentoring award
Member News

Simcox and Gisriel receive mentoring award

Aug. 25, 2025

They were honored for contributing their time, knowledge, energy and enthusiasm to mentoring postdocs in their labs.