• Crowning a quest into a very well-guarde

    From ScienceDaily@1:317/3 to All on Friday, April 08, 2022 22:30:42
    Crowning a quest into a very well-guarded secret: Structure of the
    kinetochore corona finally revealed

    Date:
    April 8, 2022
    Source:
    Max Planck Institute of Molecular Physiology
    Summary:
    During cell division in a mother cell, the 23 chromosomes that carry
    the human genome must be first copied and later delivered to two
    newly forming daughter cells. At least in healthy cells, the result
    is astonishingly flawless, and no chromosome is ever lost. Not so
    in malignant cells, where rampant chromosome segregation errors
    generate a continuous flux of new genetic variants that support
    metastatic growth and resistance to chemotherapy. A multilayered
    protein structure called the kinetochore executes the chromosome
    delivery program.



    FULL STORY ==========================================================================
    Cell division builds our bodies, supplying all cells in our tissues and
    organs, from the skin to the intestine, from the blood to the brain. It
    not only allows these organs to grow, but also to regenerate with fresh
    cells when required.

    Cell division starts with the replication of chromosomes, the carriers
    of the three billion nucleotides of the human genome.The replicated
    chromosomes are then distributed to the daughter cells in a process named mitosis. During mitosis, a network of thread-like structures named the
    mitotic spindle initially captures the chromosomes. After positioning them
    in a highly choreographed process, the spindle separates the chromosomes
    in opposite direction, so that when two cells form out of one, each
    inherits an exact copy of the genome. Even the smallest errors in this
    process will have dire physiological consequences.


    ==========================================================================
    A multilayered challenge The kinetochore is the point of contact of
    chromosomes with the spindle, and is therefore crucially involved in
    the process of chromosome alignment and partition. It is a complicated multilayered protein complex. "Understanding kinetochores is a
    tremendous challenge, as they consist of several layers, each made
    of many interacting building blocks" says Musacchio. "The outermost
    layer, the corona, has retained some of the most interesting secrets
    of the kinetochore. Its assembly is particularly interesting, since the
    complex has a brief lifetime that ends right before the critical steps of chromosome alignment and segregation." In a series of previous studies, Musacchio's laboratory made fundamental inroads into the structure and
    function of the different layers of kinetochores and how they connect chromosomes to microtubules. To gain this knowledge, the group adopted
    a reductionist approach named biochemical reconstitution. They produced
    the individual components of the protein networks outside the cell, in
    a test tube. They then reassembled them piece by piece to form an almost complete kinetochore that they could study in isolation, in a controlled
    and simplified environment that contrasts with the enormously complex,
    buzzing interior of a cell.

    Applying the same strategy, the skilled team of two postdocs, Tobias
    Raisch and Giuseppe Ciossani, two PhD students, Ennio d'Amico and
    Verena Cmentowski, and other co-workers has now been able to rebuild
    the kinetochore corona. They showed that only two components are
    sufficient for that: the ROD-Zwilch-ZW10 (RZZ) protein complex and the
    protein Spindly, which plays an essential role in the interaction of the kinetochore with the microtubules. The corona assembles exclusively on kinetochores, and the mechanisms that limit its growth to these structures
    had remained a crucial unresolved question. By reconstituting the process
    in vitro, the scientists were able to identify an enzyme, the kinase MPS1,
    as the essential catalyst of RZZ corona assembly at the kinetochore.

    One step closer to the crown Electron microscopy (EM) has accompanied
    the study of kinetochores since the 1960's, but it wasn't until recently,
    that burgeoning methodological developments made this technique able to visualize the building blocks at the atomic scale. "In 2017, we generated
    the first ever 3D structural model of the RZZ complex by cryo-EM,"
    says Raunser. "However, at the 1 nm resolution of this initial model,
    it was impossible to observe the finest molecular details responsible
    for biological function." The new structural analysis improved
    the resolution to the point that atomic details emerged, finally
    explaining how interactions of RZZ components with themselves and with
    Spindly promote corona assembly into a large polymer that surrounds the kinetochore. "Our work crowns a succession of previous studies on the kinetochore corona, now providing us with a framework to understand the critical moment of cell division when the attachment of chromosomes to microtubules becomes essentially irreversible" concludes Musacchio. The
    team's future studies will try to integrate the corona into reconstituted kinetochores, moving a new important step towards the reconstitution of chromosome segregation in vitro, a goal of extraordinary ambition that
    will shed light on the basis of a most fundamental process of life.


    ========================================================================== Story Source: Materials provided by Max_Planck_Institute_of_Molecular_Physiology. Note: Content may be edited
    for style and length.


    ========================================================================== Journal Reference:
    1. Tobias Raisch, Giuseppe Ciossani, Ennio d'Amico, Verena Cmentowski,
    Sara
    Carmignani, Stefano Maffini, Felipe Merino, Sabine Wohlgemuth,
    Ingrid R Vetter, Stefan Raunser, Andrea Musacchio. Structure
    of the RZZ complex and molecular basis of Spindly‐driven
    corona assembly at human kinetochores. The EMBO Journal, 2022;
    DOI: 10.15252/embj.2021110411 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220408103122.htm

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