The nonmotor adaptor HMMR dampens Eg5-mediated forces to preserve the kinetics and integrity of chromosome segregation

Abstract

The nonmotor adaptor protein HMMR maintains the kinetics and integrity of chromosome segregation by promoting TPX2-Eg5 complexes that dampen Eg5-mediated forces and support K-fiber stability, kinetochore–microtubule attachments, and inter-kinetochore tension. HMMR is needed to prevent the generation of aneuploid progeny cells.

Hyaluronan Mediated Motility Receptor (HMMR) Encodes an Evolutionarily Conserved Homeostasis, Mitosis, and Meiosis Regulator Rather than a Hyaluronan Receptor

“…HMMR is a largely coiled-coil protein that can bind to microtubules directly through its N-terminus [19] and localize to the centrosome through a C-terminal bZip motif [16], which is structurally very similar to the C-terminal bZip motif in Xklp2 that enables an interaction with TPX2 [16,28]. The similarity in these domain structures seeded the hypothesis that HMMR also interacts with TPX2, which has been confirmed experimentally through the study of HMMR/RHAMM in human mitotic cells [16,33,35] and Xenopus RHAMM (XRHAMM) in Xenopus meiotic extracts [32,34,36,55].…”

“…To interact with hyaluronan, CD44 and other link module-based binding proteins use tandem repeat loops with homology to the cartilage link protein [12]. HMMR, however, was shown to interact with hyaluronan in an ionic manner through a basic, 35 amino acid, C-terminal region, which can be further subdivided into two motifs of 10 amino acids and 11 amino acids, respectively [13]. These motifs correspond with human HMMR amino acids 636-646 and amino acids 658-667, which are highly basic regions that became known as Basic (B) (X)7 Basic (B X7 B) motifs [13,14] ( Figure 1A).…”

“…For HMMR, the bZip motif locates the protein to the centrosome and HMMR complexes with a significant fraction of TPX2 in a cell cycle-dependent manner [31][32][33][34]. These complexes serve to both regulate mitotic kinase activities [33] and alter Eg5 motor protein processivity [35,36].…”

“…The interaction between HMMR and TPX2 is important for Ran-dependent microtubule assembly near chromosomes [32,34], the activity of Aurora kinase A and microtubule nucleation at spindle poles [33], and the regulation of the processivity of the kinesin motor Eg5 [35,36]. The C-terminal bZip motif in Xklp2 regulates its location to microtubule minus ends in a dynein-dependent manner [28]; similarly, the C-terminal bZip motif in HMMR regulates its location to centrosomes and interaction with dynein [31].…”

Non‐canonical functions of the mitotic kinesin Eg5

“…A requirement for Eg5 during mitosis has been demonstrated experimentally in cells from multiple species. Deletion of Eg5, reduction of its expression, or inhibition of its activity results in the formation of a monopolar spindle (Fig ), leading to the activation of the spindle checkpoint and a subsequent block in cell division . The formation of a monopolar spindle upon the impairment of Eg5 supports the general consensus that the core function of Eg5 is to slide apart anti‐parallel microtubules during mitosis.…”