Uno Lindberg, who elucidated the role of the profilin:actin complex in cell motility, died June 30, 2017 at the age of 78, eight years after an unfortunate accident that left him wheelchair-bound and unable to speak or write, but attentive and communicative with a clear mind.
Lindberg was one of the pioneers of the field of cell motility. As a PhD student at the Karolinska Institute in the late 1960’s, he isolated an inhibitor of deoxyribonuclease I (DNase I) that appeared to be ubiquitous in diverse cell and tissue extracts. Later, at the Cold Spring Harbor Laboratory, he and Elias Lazarides identified the inhibitor as actin. Not only did this boost the then gradually developing view that actin–a “muscle”-protein–is a central component of all eukaryotic cells, it also formed the starting point for Lindberg’s lifelong carrier as a cell biologist.
During the second half of the 1970’s, he and his colleagues in the cell motility (CEMO)-group at Uppsala University, demonstrated that the DNase I inhibitor was, in fact, a complex of actin and that a small protein that they named profilin, due to its ability to control actin polymerization in vitro and its presumed role in stabilizing non-filamentous or profilamentous actin in non-muscle cells. This and later studies from the Lindberg laboratory, as well as from other groups, demonstrated that profilin-bound actin indeed is a major source of actin during filament formation and elongation. Initially, Uno referred to the profilin:actin complex as “profilactin.” However, given the insights of its dynamic nature, he and his colleagues began to refer to the complex as “profilin:actin” to emphasize its function as a dynamic complex.
The next major insight contributed by the Lindberg laboratory was the realization that well-ordered actin arrangements constitute the leading edge of migrating cells, forming sheet- and finger-like protrusions known today as lamellipodia and filopodia, respectively. This discovery was made possible by new techniques to fix and negatively stain cells for electron microscopy and demonstrated the close apposition of actin-containing structures with the cellular membrane. These findings suggested an essential role for actin in building and reorganizing peripheral structures, such as signal transduction and receptor complexes.
The insights from these studies, together with state-of-the-art advanced light microscopy of living cells, formed the basis for the next breakthrough–the realization that remodeling of the profilin: actin complex was intimately linked to the phosphatidylinositol receptor signaling pathway. These insights depended crucially on the DNase I-inhibition assay, which enabled non-filamentous actin to be quantitatively determined in platelets as a model system to study receptor-dependent activation of actin polymerization.
In 1981, Lindberg was appointed a professor of cell biology at the Wenner-Gren Institute, Stockholm University where he remained until his retirement in 2006, subsequently returning to the Karolinska Institute for an emeritus position. Throughout his years as an active researcher, Lindberg tirelessly dug into the molecular machinery of cell motility, preaching to colleagues and students about the importance for cell biologists to bridge the gap between the big and the small, challenging those wanting to understand cellular processes to visualize molecules, and to appreciate the structure and dynamics of macromolecules.
A major endeavor of Lindberg and one that more than anything else captivated his interest was his search for a precise molecular understanding of the actin filament in living cells. Naturally, this originated with the identification and characterization of profilin:actin. As a molecular protein biochemist with keen insights about major cell biology problems, he realized the potential of the profilin:actin complex to probe and possibly determine the molecular structure of actin. Early on, this seemed impossible because of the tendency for actin to polymerize under the salt conditions used to grow crystals needed for X-ray structure determination. Lindberg’s unique insights and unfailing ambition paved the road to a life-long and highly successful collaboration with Clarence E. Schutt, which began when Schutt was at the Laboratory of Molecular Biology (LMB), Cambridge, UK and continued unabated after he became professor of chemistry at Princeton University. In 1993 they presented the high-resolution structure of profilin:actin, the first structure of a non-muscle actin and the first of profilin. Soon afterward they published the structure of profilin alone, and in 1996 the second, so-called “open” structure of actin was determined from profilin:actin crystals pre-soaked with Mg2+-containing buffer. Later, after Lindberg’s injury, the group led by Gloria Borgstahl has advanced the understanding of the dynamics of the profilin:actin complex using crystallography to determine the multiplicity of structural states in the semi-crystalline, or incommensurate, form of profilin:actin described by Schutt and Lindberg in 1989. Borgstahl’s modeling and interpretations build on the Schutt-Lindberg model regarding the flexing of the actin molecule during binding and release of profilin and the associated nucleotide exchange (Porta et al 2017).
While solving the structure of profilin:actin, Schutt and Lindberg immediately appreciated that the organization of the crystallized complex, which comprised a flat ribbon-like actin polymer with profilin intercalating along the edges, could reflect the existence of an alternative variant of the helical actin filament to that proposed by Ken Holmes and coworkers (1990). With a combination of frustration, sadness, and in fact interlaced with some anger, the team tried hard to convince the field that the Schutt-Lindberg model was important and should be taken seriously. However, with a few exceptions, this has not fully been realized–a true disappointment for both of them, and quite possibly a setback for science. Up to the very last days before becoming incapacitated, Lindberg was preoccupied with this problem, searching new insights from the literature and trying to design experiments that would capture the potentially metastable structure of the ”actin ribbon.” More recent ideas to attack this problem by Schutt, and others that have worked closely with him and Lindberg, have as yet to be awarded funding, and consequently, whether the “actin ribbon” actually exists in vivo remains unclear.
Lindberg was a passionate teacher working hard to improve the cell biology program at all levels of specialization at Stockholm University. As a member of the Royal Swedish Academy of Sciences (RSAS), he was very active in a project aiming to improve the teaching of Natural Sciences in Swedish schools. In the early 2000’s he became Vice President (Preses) of RSAS with responsibility for its international activities and as such, he engaged in his untiring way in advocating for environmental protection and the development of a sustainable plan to preserve the planet. Lindberg also took on several missions outside the university and academy. For several years, he served Folkuniversitetet in their work to disseminate new research to the general public and was among a group of scientists in the 1980’s that founded a European research network for the cell motility field, the European Cytoskeletal Forum (ECF), where he was a board member until 2002. Finally, he had been a proud member of the American Society for Cell Biology since 1990 and had a large network of friends among American cell biologists, who together with the openness of their scientific discussions, served as a strong inspiration to him.
Those of us who had the privilege to know Uno Lindberg remember him as a generous and humorous person that never tired of learning more about the world and appreciating the nature around him, whether it be understanding how cells move, what birds sing to us returning from the dark winter, or who would be the next skiing champion in the coming season. He was a true scientist, asking the most penetrating questions and surely living up to his motto, “Always ask how do we know what we know.” He spent long hours reading (which he called “archive work”) aimed at learning how the contemporary understanding of scientific issues had developed, from original discoveries to current status via crucial experiments. In many aspects, his knowledge was encyclopedic and, along with his energy, passion, and joy of life, he was a great beacon for students, colleagues, and friends. He is survived by his wife, Ann Margret, their two daughters Anna-Karin and Rebecka, and grandchildren. Needless to say, he is greatly missed, and never to be forgotten as long as cell biologists pursue the large and the small.
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