An unstructured protein as a dog-leash

19. January 2022

A key process of all cellular life is cell division, in which the genetic material of one cell is duplicated and divided into two daughter cells. The duplicated chromosomes align in the cell center and are positioned there by cellular filaments, the microtubules. This chromosome-microtubule binding is established and carefully fine-tuned by large protein complexes, the so-called kinetochores. Wrongly attached chromosomes must be first disengaged and reattached to ensure equal separation of the genetic material. One essential player in this error correction mechanism is the inner centromere protein (INCENP), which contains a long, unstructured region (IDR, intrinsically disordered region). The function of this domain, which can be highly modified by phosphorylation, is widely unknown.

Using molecular dynamics simulations, both on the atomic scale as well as on a coarser level, researchers from the MBM group investigated the effect of phosphorylation on this domain. They found that phosphorylation enlarges the dimensions of the IDR mainly by introducing negative charges. With phosphorylation, the IDR shifts from collapsed conformations, characterized by many internal contacts, to weakly interacting stretched states. In this way, phosphorylation also tunes the cohesiveness of several INCENP molecules interacting with each other. These data suggest that the INCENP IDR might act as a phosphorylation-tuned and length-variable component within the so called “dog-leash model”, which was proposed by previous studies (Krenn et al. 2015). Here, the kinase Aurora B, responsible for detaching wrong chromosomes, is regulated by a “dog-leash”, which controls the distance of Aurora B to target molecules. Thus, phosphorylation of the INCENP IDR might be one way to determine the action radius of Aurora B.

Phosphorylation tunes elongation of intrinsically disordered region of the inner centromere protein (INCENP).  INCENP, a component of kinetochores, contains a large intrinsically disordered region. Our study computationally identified INCENP’s disordered region to transition between collapsed conformations (small radius and many internal contacts) and a stretched conformation (large extension with few contacts) driven by extensive phosphorylations. Thus, INCENP is proposed to take part in a so called “dog-leash” that allows the important kinase Aurora B to reach its outer kinetochore targets.

Check out the paper: Martin, Aponte-Santamaría, et al. “Phosphorylation tunes elongation propensity and cohesiveness of INCENP’s intrinsically disordered region”. J Mol Biol. 434: 167387 (2022).

Additional reference: Krenn, Veronica, Musacchio, Andrea. “The aurora b kinase in chromosome bi-orientation and spindle checkpoint signaling.” Front. Oncol. 5, 225. (2015).

About HITS

The Heidelberg Institute for Theoretical Studies (HITS) was established in 2010 by the physicist and SAP co-founder Klaus Tschira (1940-2015) and the Klaus Tschira Foundation as a private, non-profit research institute. HITS conducts basic research in the natural sciences, mathematics and computer science, with a focus on the processing, structuring, and analyzing of large amounts of complex data and the development of computational methods and software. The research fields range from molecular biology to astrophysics. The shareholders of HITS are the HITS-Stiftung, which is a subsidiary of the Klaus Tschira Foundation, Heidelberg University and the Karlsruhe Institute of Technology (KIT). HITS also cooperates with other universities and research institutes and with industrial partners. The base funding of HITS is provided by the HITS Stiftung with funds received from the Klaus Tschira Foundation. The primary external funding agencies are the Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG), and the European Union.

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