Recently, the research team led by Professor Chen Zhiming from University of South China confirmed that the GAK-Hsc70 complex drives plasma membrane invagination by promoting the remodeling of nascent clathrin lattices. The relevant findings were published in PNAS (Proceedings of the National Academy of Sciences of the United States of America). Professor Chen Zhiming of USC and Academician Sandra L. Schmid of the National Academy of Sciences serve as co-corresponding authors of the paper, while He Zhangping, a doctoral candidate in Basic Medicine at USC, is the first author.

Clathrin-mediated endocytosis (CME) is a crucial cellular process responsible for mediating the internalization of various cargo molecules, including nutrients, signaling receptors, transmembrane ion channels, and transporters. Its dysfunction is associated with multiple diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases.CME initiates with clathrin assembling into clathrin-coated pits (CCPs) on the plasma membrane, which then invaginate, close, and bud off from the membrane to form clathrin-coated vesicles (CCVs) encapsulating cargo.Findings from total internal reflection fluorescence microscopy (TIR-FM) in live cells show that a significant proportion of initial CCPs (termed "abortive CCPs") fail and rapidly disassemble at different stages of maturation. The critical phase for forming effective pits requires early curvature generation and CCP invagination. Short-lived abortive pits typically exhibit low fluorescence signals and a flat morphological feature.Electron microscopy (EM) studies indicate that flat clathrin lattices are composed almost entirely of hexagonal arrays, while curved lattices contain both hexagonal and pentagonal structures. Although some intermediate structures have been observed and are thought to represent the hexagonal-to-pentagonal transition needed for curvature, this view remains controversial. Moreover, the molecular mechanism driving the flat-to-curved transition of clathrin lattices has remained unclear—a major "mystery" in biomedicine that urgently needs to be unraveled.

Led by Professor Chen Zhiming, the research team tackled the key scientific questions mentioned above and discovered/confirmed that:Knocking out the GAK gene (cyclin G-associated kinase) inhibits the stabilization and invagination of CCPs (clathrin-coated pits).When mutations in the J domain of GAK prevent the recruitment and activation of heat shock protein Hsc70 at CCPs, it triggers abnormal accumulation of GAK on CCPs, hinders CCP stabilization and invagination, and significantly increases the proportion of highly transient abortive CCPs.These findings reveal the molecular mechanism of clathrin lattice remodeling, supporting the hypothesis that the GAK-Hsc70 complex promotes the flat-to-curved transition required for CME (clathrin-mediated endocytosis) by facilitating clathrin triskelion turnover and lattice remodeling. This work lays an important theoretical foundation for deciphering the mechanisms underlying the occurrence and development of related diseases.