Biology subjects

Kops, G.

Publications and source records attributed to Kops, G..

3 recordsLinked to original sources

bioRxiv2020

The MPS1 kinase NTE region has helical propensity and preferred conformations towards the TPR domain

The mitotic spindle assembly checkpoint (SAC) ensures accurate segregation of chromosomes by preventing onset of anaphase until all chromosomes are properly attached to spindle microtubules. The Monopolar spindle 1 (MPS1) kinase is one of the SAC components, localizing at unattached kinetochores by an N-terminal localization module. This module comprises a flexible NTE module and the TPR domain, which we previously characterized for their contribution to kinetochore binding. Here we discuss the conformations of the highly flexible NTE with respect to the TPR domain, using paramagnetic NMR. The distance restraints derived from paramagnetic relaxation enhancements (PREs) show that the mobile NTE can be found in proximity of a large but specific part of the surface area of the TPR domain. To sample the conformational space of the NTE in the context of the NTE-TPR module, we used the ab initio Rosetta approach supplemented by paramagnetic NMR restraints. We find that many NTE residues have a propensity to form helical structures and that the module localizes at the convex surface of the TPR domain. This work demonstrates the highly dynamic nature of the interactions between the NTE and TPR domains and it shows that the convex rather than the canonical concave TPR surface mediates interactions, leading to the auto-inhibition that the TPR exerts upon the NTE region in the context of SAC signaling.

biochemistry↗

bioRxiv2019

Degree and site of chromosomal instability define its oncogenic potential

Most human cancers are aneuploid, due to a chromosomal instability (CIN) phenotype. Despite being hallmarks of cancer, however, the roles of CIN and aneuploidy in tumor formation have not unequivocally emerged from animal studies and are thus still unclear. CIN can both promote and suppress tumorigenesis, but variances in mechanisms and timings of CIN induction in different oncogenic backgrounds and associated tissues limit interpretation of the contributions of CIN. Using a novel conditional mouse model for diverse degrees of CIN, we find that a particular range is sufficient to drive very early onset spontaneous adenoma formation in the intestine, showing that CIN can act as a much more potent oncogenic driver than was previously reported. In mice predisposed to intestinal cancer (ApcMin/+), moderate but not low CIN causes a remarkable increase in adenoma burden in the entire intestinal tract, especially in the distal colon, more closely modelling human disease. Strikingly, high levels of CIN promote adenoma formation in the distal colon even more than moderate CIN does, but have no effect in the small intestine. Our results thus show that CIN can be potently oncogenic, but that certain levels of CIN can have contrasting effects in distinct tissues.

cancer biology↗

bioRxiv2019

Mosaic origin of the eukaryotic kinetochore

The emergence of eukaryotes from ancient prokaryotic lineages was accompanied by a remarkable increase in cellular complexity. While prokaryotes use simple systems to connect DNA to the segregation machinery during cell division, eukaryotes use a highly complex protein assembly known as the kinetochore. Although conceptually similar, prokaryotic segregation systems and eukaryotic kinetochore proteins share no homology, raising the question of the origins of the latter. Using large-scale gene family reconstruction, sensitive profile-versus-profile homology detection and protein structural comparisons, we here reveal that the kinetochore of the last eukaryotic common ancestor (LECA) consisted of 52 proteins that share deep evolutionary histories with proteins involved in a few prokaryotic processes and a multitude of eukaryotic processes, including ubiquitination, chromatin regulation and flagellar as well as vesicular transport systems. We find that gene duplications played a major role in shaping the kinetochore: roughly half of LECA kinetochore proteins have other kinetochore proteins as closest homologs. Some of these (e.g. subunits of the Mis12 complex) have no detectable homology to any other eukaryotic protein, suggesting they arose as kinetochore-specific proteins de novo before LECA. We propose that the primordial kinetochore evolved from proteins involved in various (pre-)eukaryotic systems as well as novel proteins, after which a subset duplicated to give rise to the complex kinetochore of LECA.

cell biology↗