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Molecular mechanism of condensin I activation by KIF4A.

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Title: Molecular mechanism of condensin I activation by KIF4A.
Authors: Cutts, Erin E, Tetiker, Damla, Kim, Eugene, Aragon, Luis
Source: EMBO Journal; Feb2025, Vol. 44 Issue 3, p682-704, 23p
Subject Terms: CELL cycle regulation, CONDENSIN, PEPTIDES, COHESINS, BINDING sites
Abstract: During mitosis, the condensin I and II complexes compact chromatin into chromosomes. Loss of the chromokinesin, KIF4A, results in reduced condensin I association with chromosomes, but the molecular mechanism behind this phenotype is unknown. In this study, we reveal that KIF4A binds directly to the human condensin I HAWK subunit, NCAPG, via a conserved disordered short linear motif (SLiM) located in its C-terminal tail. KIF4A competes for NCAPG binding to an overlapping site with SLiMs at the N-terminus of NCAPH and the C-terminus of NCAPD2, which mediate two auto-inhibitory interactions within condensin I. Consistently, the KIF4A SLiM peptide alone is sufficient to stimulate ATPase and DNA loop extrusion activities of condensin I. We identify similar SLiMs in the known yeast condensin interactors, Sgo1 and Lrs4, which bind yeast condensin subunit, Ycg1, the equivalent HAWK to NCAPG. Our findings, together with previous work on condensin II and cohesin, demonstrate that SLiM binding to the NCAPG-equivalent HAWK subunit is a conserved mechanism of regulation in SMC complexes. Synopsis: How loss of KIF4A chromokinesin reduces chromosome association of condensin has remained unclear. This study demonstrates that human condensin I is auto-inhibited by short linear motifs (SLiMs) in its NCAPH and NCAPD2 subunits binding to the NCAPG subunit, and that this interaction can be competed away by a SLiM in KIF4A. Deletion of either NCAPG, NCAPD2, the disordered C-terminus of NCAPD2, or the disordered N-terminus of NCAPH increases ATP turnover by condensin I. The disordered regions of NCAPD2 and NCAPH contain SLiMs that bind directly to NCAPG. The KIF4A C-terminal region contains a NCAPG-binding SLiM that may compete directly with the inhibitory SLiMs in NCAPD2 and NCAPH. A KIF4A SLiM peptide is sufficient to increase condensin I ATPase activity and promote DNA loop extrusion by condensin I. The NCAPG SLiM binding site is conserved in the yeast condensin subunit, Ycg1, interacting with SLiMs in Lrs4 and SgoI. Short linear motifs (SLiMs) binding to condensin complex HAWK subunits mediate an auto-inhibitory interaction that can be competed away by a SLiM in human KIF4A. [ABSTRACT FROM AUTHOR]
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Abstract:During mitosis, the condensin I and II complexes compact chromatin into chromosomes. Loss of the chromokinesin, KIF4A, results in reduced condensin I association with chromosomes, but the molecular mechanism behind this phenotype is unknown. In this study, we reveal that KIF4A binds directly to the human condensin I HAWK subunit, NCAPG, via a conserved disordered short linear motif (SLiM) located in its C-terminal tail. KIF4A competes for NCAPG binding to an overlapping site with SLiMs at the N-terminus of NCAPH and the C-terminus of NCAPD2, which mediate two auto-inhibitory interactions within condensin I. Consistently, the KIF4A SLiM peptide alone is sufficient to stimulate ATPase and DNA loop extrusion activities of condensin I. We identify similar SLiMs in the known yeast condensin interactors, Sgo1 and Lrs4, which bind yeast condensin subunit, Ycg1, the equivalent HAWK to NCAPG. Our findings, together with previous work on condensin II and cohesin, demonstrate that SLiM binding to the NCAPG-equivalent HAWK subunit is a conserved mechanism of regulation in SMC complexes. Synopsis: How loss of KIF4A chromokinesin reduces chromosome association of condensin has remained unclear. This study demonstrates that human condensin I is auto-inhibited by short linear motifs (SLiMs) in its NCAPH and NCAPD2 subunits binding to the NCAPG subunit, and that this interaction can be competed away by a SLiM in KIF4A. Deletion of either NCAPG, NCAPD2, the disordered C-terminus of NCAPD2, or the disordered N-terminus of NCAPH increases ATP turnover by condensin I. The disordered regions of NCAPD2 and NCAPH contain SLiMs that bind directly to NCAPG. The KIF4A C-terminal region contains a NCAPG-binding SLiM that may compete directly with the inhibitory SLiMs in NCAPD2 and NCAPH. A KIF4A SLiM peptide is sufficient to increase condensin I ATPase activity and promote DNA loop extrusion by condensin I. The NCAPG SLiM binding site is conserved in the yeast condensin subunit, Ycg1, interacting with SLiMs in Lrs4 and SgoI. Short linear motifs (SLiMs) binding to condensin complex HAWK subunits mediate an auto-inhibitory interaction that can be competed away by a SLiM in human KIF4A. [ABSTRACT FROM AUTHOR]
ISSN:02614189
DOI:10.1038/s44318-024-00340-w