Adenylate Kinase Isoform Network: A Major Hub in Cell Energetics and Metabolic Signaling - Systems Biology of Metabolic and Signaling Networks - page 149

(Fratelli et al. 2002 ; Ginger et al. 2005 ; Janssen et al. 2004 ; Klier et al. 1996 ; Rahlfs
et al. 2009 ; Shi et al. 2008 ).
The AK6 isoform was identified to be localized to the cell nucleus, where energy
provision and nucleotide channeling into DNA synthesis play critical roles in
processing genetic information (Dzeja et al. 2002 ; Ren et al. 2005 ; Zhai
et al. 2006 ). However, there is still controversy regarding the AK6 isoform,
which is also known as TAF9 RNA polymerase II possessing ATPase activity
(Santama et al. 2005 ), suggesting that other adenylate kinase isoforms (AK1 and
AK5) can also subserve nuclear energetic needs (Dzeja et al. 2002 ; Janssen
et al. 2004 ; Noda 1973 ). AK5 may associate with centrosomes (unpublished).
Knockdown of AK6 slows growth and development of C. elegans (Zhai
et al. 2006 ), while in yeast, a point mutation in the Fap7 gene, an analog of AK6,
reduces growth on glucose (Juhnke et al. 2000 ). Through biochemical purification
and mass spectrometry analysis, a putative homolog of the S. cerevisiae Rps14
protein was identified as a partner of AK6 (Feng et al. 2012 ). Most importantly,
aak6 T-DNA insertion mutants had decreased stem growth compared with wild-
type plants. These data indicate that AAK6 exhibits adenylate kinase activity and is
an essential growth factor in Arabidopsis (Feng et al. 2012 ). In this regard,
TcADKn is involved in ribosome biogenesis, being involved in the processing of
the 18S precursor at site D by directly interacting with TcRps14 (Camara Mde
et al. 2013 ). Another nuclear protein Rad50, a member of DNA repair RAD50/
MRE11/NBS1 protein complex (MRN), which is essential for sensing and signal-
ing from DNA double-strand breaks, in addition to ATP binding and hydrolysis,
may have intrinsic or associated adenylate kinase activity required for efficient
tethering between different DNA molecules (Bhaskara et al. 2007 ; Randak
et al. 2012 ). A mutation affecting ATPase/adenylate kinase activity of Rad50,
necessary for DNA tethering, also abolishes the formation of viable spores
(Bhaskara et al. 2007 ). Thus, adenylate kinase and adenylate kinase activity-
possessing proteins play a significant role in the energetics of the nucleus which
is separated from major ATP generating processes in the cytosol.
Recently, it was demonstrated that AK1 translocates to the nucleus during cell
division and associates with the mitotic spindle to provide energy for chromosome
disjunction (Fig. 6.2 ) (Dzeja et al. 2011a ). The discovery of nuclear translocation of
AK1 in metaphase is in line with the adenylate kinase role in energy support of
motility of cilia and flagella which have 9 + 2 microtubular structures similar to
those of mitotic spindle (Cao et al. 2006 ; Wirschell et al. 2004 ). In mitotic spindles,
AK1 is expected to associate with motor or anchoring proteins as it does with the
Oda5 protein of the dynein complex in flagella to provide “on-site” ATP fueling
capacity (van Horssen et al. 2009 ; Wirschell et al. 2004 ). In yeasts, AK1 interacts
with TEM1, a component of the whole network of cell cycle regulation, including
AMN1, BUB2, ARP2, TORC2, BFA1, and many others (Szappanos et al. 2011 ;
Tarassov et al. 2008 ). Beside TEM1, AK1 interacts with CLB2, Rad53, SPL2, and
PHO85, which are involved in cell cycle regulation and others (Ho et al. 2002 ). Our
studies revealed several new candidate proteins for the AK1 and AK2 interactomes
that include cell motility, cell cycle, and cytokinesis-associated proteins, like