Making sense of low- complexity domains: The 2025 Lasker Basic Science Award

• 成果类型: Article
• 署名作者: Kaelin Jr, William G.
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14488
• DOI: 10.1073/pnas.2519778122
• 发表日期: 2025-09-16
• 关键词: nuclear-pore complex; fg-repeat; permeability; nucleoporins; hydrogel; binding; import; ntf2; transport; interacts

摘要

Up to 10 to 20% of the proteome contains regions with much lower amino acid diversity than would be expected by chance. This year's Lasker Basic Science Award is given to Steven McKnight and Dirk G & ouml;rlich for their pioneering work on such low- complexity domains (LCDs). They showed, using a variety of elegant approaches, that such LCDs can form homotypic and heterotypic interactions that lead to reversible phase separations in cells. These phase separations, which in the laboratory manifest as hydrogels and in cells as membrane free structures (liquid condensates) such as P bodies and stress granules, form hubs for molecular processes such as transcription and messenger RNA (mRNA) splicing and also underlie the selectivity of nuclear pore complexes (NPCs), which act a barriers to large molecules unless they are escorted by specific LCD containing nuclear transporters that interact with LCD containing nucleoporins within NPC channels. Naturally occurring LCD mutations linked to neurodegeneration and other diseases cause the formation of irreversible (rather than reversible) LCD polymers, resulting in insoluble, amyloid- like, fibrils, underscoring the critical importance of these domains.