Moonlighting Function of the Tubulin Cytoskeleton: Macromolecular Architectures in the Cytoplasm - Systems Biology of Metabolic and Signaling Networks - page 166

7.3 Sensor Potency of Enzyme-Decorated Microtubules

Cells are confronted with the challenge of generating a single phenotype that must
be coherent with a huge number of combinations of internal and external
conditions. Generating the meaningful outputs required for these phenotypes entails
sensing and integrating a wide diversity of chemical and physical information, and
hence the coordination of metabolic and signaling processes. We have proposed
that this sensing, integration, and coordination is achieved by the complex
structures and moonlighting functions of

the cytoskeletal network (Norris

et al. 2010 ; Norris et al. 2013 ).
In this proposal, the direction and potency of the sensing would be determined
by the structure-related changes of the cytoskeletal network in response to the
activity of individual macromolecules—along with associated metabolites and
nucleotides—inside the living cell (Fig. 7.4 ). These responses comprise the binding
of these macromolecules to the cytoskeleton and the consequences of this binding
on the behavior of both partners, i.e., cytoskeleton dynamics and the catalytic and
regulatory properties of the individual proteins (and/or their specific complexes).
The binding of macromolecules to the cytoskeleton is of specific importance in the
regulation at a higher level via the formation of microcompartments in linear
pathways or at metabolic crossroads. In addition, nucleotides such as ATP and
GTP, which can both influence and respond to cytoskeleton-mediated events, play
key roles in many metabolic and signaling pathways.
If the binding by the cytoskeleton of an enzyme increases its activity, it may well
be that an enzyme that is catalytically active has a higher probability of binding to
the cytoskeleton. Microtubule binding to glycolytic enzymes is known to alter the
catalytic and regulatory properties of several enzymes [see Table 1 in Ovadi
et al. ( 2004 )]. Such binding increases HK activity to enhance the glycolytic flux
in brain tissue (although this does not influence MT dynamics and structure). MT
binding to PFK decreases the activity of the enzyme and results in a periodic cross-
linking of the MTs. (cf. Fig. 7.1 ). MT binding to PK impedes MT assembly (but
does not influence the activity of the enzyme). Moreover, the binding by MTs of
individual enzymes is influenced by enzyme-enzyme interactions. For example, the
assembly of PFK into an aldolase-PFK complex (where it is no longer subject to
allosteric regulation) counters the association of PFK with MTs (Ovadi et al. 2004 ).
A two-way relationship exists between cytoskeleton-enzyme association and
nucleoside triphosphate levels in which (1) the changing dynamics of the cytoskel-
etal filaments that result from enzyme association modifies nucleoside triphosphate
levels and (2) changing nucleoside triphosphate levels modify the dynamics and
hydrolytic activity of the cytoskeleton. For example, the efficiency of MT
treadmilling depends on GTP concentration whilst MT dynamics depends on MT
motor proteins (like Kin-I kinesins), which hydrolyze ATP (Moore and Wordeman
2004 ). Reciprocally, there is some evidence that cytoskeletal dynamics affects the
levels of the nucleoside triphosphates. GTP hydrolysis, for example, depends on
tubulin polymerization and is stimulated by MAPs (Sloboda et al. 1976 ). Moreover,