Ran in Mitosis - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 137

centromeric chromatin region until anaphase onset. The widely accepted model of
Aurora B function implies that it phosphorylates several outer kinetochores proteins
in the vicinity of the kinase to modulate their MT binding behaviour. Stable, end-on
MT binding to kinetochores, however, generates tension and drags away the sub-
strates from the source of phosphorylation, which further stabilises MT kinetochore
interaction (Liu et al. 2009 ). Recent FRET experiments in intact cells suggest that
the Aurora B and RanGTP gradients cooperate to ensure efficient spindle formation
(Lee et al. 2012 ) and it will be interesting in the future to unravel the molecular
details about this communication.
7.7 Evolution of the Ran System
Evolution of the nuclear compartment marks the development of eukaryotic cells.
A diffusible gradient of RanGTP interacting with Ran responsive receptors around
chromosomes, however, may have evolved prior to the closed nucleus. Like todays
transport receptors, these receptors could have served as chaperones or regulators
for the function of bound substrates. Efficient binding of Ran's exchange factor to
chromatin and strictly localised Ran guanine nucleotide exchange on chromatin
generated a compartment defined by high RanGTP concentration and active nuclear
proteins without the boundary of the NE. After release from their receptors, actual
binding to destined structures on chromatin may have restricted diffusion and may
have allowed specific functions of active nuclear proteins. The system certainly
became much more efficient when the NE closed and NPCs evolved together with
FG repeats and a new set of transport receptors, in which chaperone activity for
nuclear proteins, Ran responsiveness and solubility in the hydrophobic environ-
ment of NPCs were combined. From this perspective, open mitosis might possibly
be viewed as a cell biological fossil, overcome by many simple eukaryotes. A
compact, comparatively small genome and an evolutionary optimization through
countless generations could have allowed the development of closed mitosis, which
enabled efficient separation of cytoplasmic and nuclear functions throughout the
cell cycle. Interestingly, the highly conserved nucleoporin Mel28/ELYS displays a
complicated primary structure in metazoan cells with, e.g., 2,275 amino acids in
humans, whereas a minimal version of this nucleoporin with 298 amino acids in
S. pombe is bearing only the motif required for incorporation into NPCs (i.e. ELY
domain) but misses all additional sequence elements whose evolution correlates
with open mitosis (Yokoyama et al. 2014 ).