The Calcium-Dependent Interaction between S100B and the Mitochondrial AAA ATPase ATAD3A and the Role of This Complex in the Cytoplasmic Processing of ATAD3A

Abstract

S100 proteins comprise a multigene family of EF-hand calcium binding proteins that engage in multiple functions in response to cellular stress. In one case, the S100B protein has been implicated in oligodendrocyte progenitor cell (OPC) regeneration in response to demyelinating insult. In this example, we report that the mitochondrial ATAD3A protein is a major, high-affinity, and calcium-dependent S100B target protein in OPC. In OPC, ATAD3A is required for cell growth and differentiation. Molecular characterization of the S100B binding domain on ATAD3A by nuclear magnetic resonance (NMR) spectroscopy techniques defined a consensus calcium-dependent S100B binding motif. This S100B binding motif is conserved in several other S100B target proteins, including the p53 protein. Cellular studies using a truncated ATAD3A mutant that is deficient for mitochondrial import revealed that S100B prevents cytoplasmic ATAD3A mutant aggregation and restored its mitochondrial localization. With these results in mind, we propose that S100B could assist the newly synthesized ATAD3A protein, which harbors the consensus S100B binding domain for proper folding and subcellular localization. Such a function for S100B might also help to explain the rescue of nuclear translocation and activation of the temperature-sensitive p53val135 mutant by S100B at nonpermissive temperatures.

ATAD3, a vital membrane bound mitochondrial ATPase involved in tumor progression

“…ATAD3 membrane topology is now nearly elucidated but doubts remain concerning the exact localization of the N-terminus (Gilquin et al 2010a;Gilquin et al 2010b;Fang et al 2010). The C-terminus is located in the mitochondrial matrix and could be associated with the nucleoid (mitochondrial DNA and associated proteins) but this interaction may be indirect (Bogenhagen et al 2008).…”

Genetic and Epigenetic Mechanisms in Down Syndrome Brain

“…In addition, other HSA21 genes may indirectly affect this pathway. Alternatively, HSA21 gene S100B may target mitochondrial proteins such as p53 and ATPase ATAD3A, thereby assisting the cytoplasmic processing of proteins for proper folding and subcellular localization [117][118][119][120][121]. Another HSA21 gene APP and its product beta amyloid can interact with import receptors to gain entry into mitochondrial compartment, where they accumulate and affect the normal function of this pathway [122,123].…”

Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

“…S100B is another HSA21 gene that can increase ROS, it is a calcium binding protein that affects calcium-dependent signals, targeting mitochondrial proteins such as p53 and ATPase ATAD3A, thereby assisting the cytoplasmic processing of proteins for proper folding and subcellular localization. S100B overexpression can also lead to p53 inactivation (Donato, 2003;Gilquin et al, 2010;Leclerc et al, 2010;Lin et al, 2001;Mihara et al, 2003). Finally, similar mechanisms involving mitochondrial dysfunction have been proposed with other HSA21 genes including SOD1 and BATCH1 (Arbuzova et al, 2002;Ferrando-Miguel et al, 2003;Furuta et al, 1995;Harris-Cerruti et al, 2004;Iannello et al, 1999;Lott et al, 2006;Shim et al, 2003).…”

“…Imbalance of excitatoryinhibitory neuronal transmission (Best et al, 2007;Cramer et al, 2010;Harashima et al, 2006) ETS2 APP Increased neuronal apoptosis, increased APP production, mitochondrial dysfunction (Helguera et al, 2005;Wolvetang et al, 2003a;Wolvetang et al, 2003b) PCP4 Calmodulin (Kleerekoper and Putkey, 2009;Thomas et al, 2003;Utal et al, 1998) DSCAM Overexpression in Purkinje cells, cortical neurons and senile plaques (Hattori et al, 2007;Saito et al, 2000;Yamakawa et al, 1998 (Dorval et al, 2007;Gardiner, 2006;Holmstrom et al, 2003) www.intechopen.com (Esposito et al, 2008a;Esposito et al, 2008b;Gilquin et al, 2010;Lin et al, 2001;Mori et al, 2010;Reeves et al, 1994) Furthermore, a DS patient with duplication of the distal last 12Mb of HSA21 (a fragment that does not include APP) did not develop typical AD pathology (Prasher et al, 1998 ). The contiguous genes are thought to be sufficient to replicate the DS features including craniofacial abnormalities, short stature, joint hyperlaxity, hypotonia and mental retardation (Delabar et al, 1993;Korenberg, 1990;Korenberg, 1993;McCormick et al, 1989;Olson et al, 2004a;Rahmani et al, 1989).…”