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"Multidisciplinary Scholar" Dirk Görlich: mystery discovered on how proteins regulate the "gateway" to the cell nucleus

Date Oct. 13, 2022

This article is a translation of a Chinese report by Xu Qimin of Wenhui Daily on September 29, with excerpts.

Proteins are essential substances and carry the mystery of life. There are 23 pairs of chromosomes in the human body. They carry genetic information inside the nucleus of each cell and are responsible for coding for proteins that catalyze biochemical reactions. To produce these proteins, substances must be transported between the cytoplasm and the nucleus. The key person who unlocked the mechanism of this mysterious “communication” is Dirk Görlich. This German biochemist has received the first WLA Prize in Life Science or Medicine for his “key discoveries elucidating the mechanism and selectivity of protein transport between the cytoplasm and nucleus”.

In the past eight years, Görlich’s papers have been cited multiple times across the globe with an ever increasing number of citations year over year. At present, the research on the mechanism of protein transport in the gel-like structure has exerted a profound influence on relevant basic research and clinical applications.
 

The discovery of gel-like proteins creating a hot research focus in cell biology

How the cell nucleus gateway functions has long been a mystery. Zhu Xueliang, a researcher at the Center for Excellence in Molecular Cell Science, the Chinese Academy of Sciences, explained that the nucleus is surrounded by a double membrane that has pores for the import or export of substances. Numerous scientists have explored the nuclear pores in the membrane and presented many delicate structures, but the mechanism of that process remained unknown until Görlich’s discovery.

The difficulty was that the cell nucleus “gateway” is a gel-like molecular network shaped by large complexes of proteins without a fixed structure. In around 2006, Görlich identified them for the first time, and clearly demonstrated the mechanism by which nuclear pores control the import or export of substances. This network, which spans the nuclear membrane, is full of pores of various sizes, and only allows molecules below a certain size to pass through.

Randy Schekman, Chairman of the WLA Prize Selection Committee in Life Science or Medicine and 2013 Nobel Prize Laureate, said that the selectivity of protein transport between the cytoplasm and the nucleus of a cell was discovered very early on, even before Görlich began his work. However, how proteins are recognized and selected for import or export and how they pass through nuclear pores remained unknown. It was not until Görlich discovered the protein molecule that he called importin that is responsible for recognizing a signal on the nuclear protein and independently acquired several basic findings that transformed this research area .

"Görlich's series of studies fundamentally elucidated how proteins enter and exit the nuclear membrane, and used phase separation, which was a very novel approach to demonstrate the mechanism of this 'gateway'," Zhu Xueliang said. In recent years, phase separation — the concentration of dissolved biological macromolecules into droplets or gels — has also become a hot trend in cell biology. Scientists have discovered that some macromolecular complexes known as "membraneless organelles" take shape and perform key functions through phase separation.

Schekman believed that the discovery of nuclear pore complexes in a gel-like state really makes Görlich's research original. "It is this gel-like substance that enables RNA molecules and small proteins in the cytoplasm to pass through pores," he said.

 

Showing strong interest in interdisciplinary studies while striving for breakthroughs

This conscientious scientist shows a strong interest in multidisciplinary research. The cytoplasm-nucleus transport study requires a profound understanding of cell biology, while the nuclear protein study incorporates concepts from multiple disciplines such as structural biology, cytoplasm-nucleus transport, and receptors.

Yang Wei, an academician of the Chinese Academy of Sciences and a foreign academician of the National Academy of Engineering, revealed that Görlich’s latest discovery shows that COVID-19 antibodies from alpaca, is 1,000 times more effective than previously developed such nanobodies. This new antibody is the first antibody with both strong stability and notable efficacy, against multiple COVID-19 mutants, according to Görlich in a 2021 release by the Max-Plank Institute for Multisciplinary Sciences(MPINAT) where he still works a director.

The extension of contemporary science is the set of multidisciplinary and interdisciplinary studies which spawn new discoveries, new technologies, and new solutions. Another joint study that Görlich engages in requires him to clarify how muscle is formed, and how it functions at the molecular level over the next five or six years. The European Research Council (ERC) has awarded the research project one of the rare and highly endowed Synergy Grants totaling EUR11 million, MPINAT release October, 2019.

Muscle is composed of bundles of muscle fibers, and each muscle tissue contains hundreds of muscle fibers. Muscle contraction is controlled by delicate structures which involve the interaction of numerous proteins. Misplacement or mismatch of these components can cause serious muscle or heart diseases.

Skeletal or cardiac muscles must be maintained throughout life to ensure their proper functions. However, how this works remains unknown. That is why it is crucial to investigate and compare the composition and the structure of sarcomeres in young and aged muscles, as Görlich explained.

This project pursues innovation in interdisciplinary studies. Through the combination of quantitative proteomics and nanobody engineering with super-resolution microscopy, cryo-electron chromatography, as well as biochemical and functional genetic analysis of muscle dynamics for fruit flies, zebrafish, and guinea pigs, the project is intended to gain new insights into the molecular structure of muscle cells, which will contribute to a better understanding of muscle diseases and to the development of new drugs to treat muscle and aging problems.