The YTA10–12 Complex, an AAA Protease with Chaperone-like Activity in the Inner Membrane of Mitochondria

Abstract

The mitochondrial members of the highly conserved AAA family, Yta10p and Yta12p, constitute a membrane-embedded complex of about 850 kDa. As an ATP dependent metallopeptidase (AAA protease), the YTA10-12 complex mediates the degradation of nonassembled inner membrane proteins. In contrast to nucleotide-dependent complex formation and substrate binding, proteolysis of bound polypeptides depends on the hydrolysis of ATP and the metallopeptidase activity of both subunits. Independent of its proteolytic function, the chaperone-like activity of the YTA10-12 complex is required for assembly of the membrane-associated ATP synthase. We propose that proteolytic and chaperone-like activities in the YTA10-12 complex mediate assembly and degradation processes of membrane protein complexes and thereby exert key functions in the maintenance of membrane integrity.

The Evolution of the Conserved ATPase Domain (CAD): Reconstructing the History of an Ancient Protein Module

“…Both the ATPase activity and Zn-binding activity are required for the correct functioning of these proteins (Weber et al 1996). Members of this protein group have been shown to degrade transcription factors such as 32 (Tomoyasu et al 1995;Herman et al 1995) and phage cII (Arlt et al 1996) protein and probably participate in a number of other cellular functions as well. The E. coli ftsH protein, for example, is also involved in bacterial septum formation (Santoss and De Almeida et al 1975), probably via secretory processes (Kihara et al 1995; Akiyama et al 1996).…”

“…Mutations in the three yeast genes that encode these proteins result in multiple defects in mitochondrial function. Two of these proteins, Rcalp (‫ס‬Yta12) and Afg3p (‫ס‬Yta10), form an 850-kD complex anchored in the inner mitochondrial membrane that apparently does not contain any additional proteins (Arlt et al 1996). These proteins are probably involved in protein degradation; an additional role as molecular chaperone has also been suggested for these proteins, as assembly of respiratory complexes appears to also require metalloprotease function (Arlt et al 1996).…”

“…Two of these proteins, Rcalp (‫ס‬Yta12) and Afg3p (‫ס‬Yta10), form an 850-kD complex anchored in the inner mitochondrial membrane that apparently does not contain any additional proteins (Arlt et al 1996). These proteins are probably involved in protein degradation; an additional role as molecular chaperone has also been suggested for these proteins, as assembly of respiratory complexes appears to also require metalloprotease function (Arlt et al 1996). The organellar localization and evolutionary relationship of these eukaryotic proteins with the eubacterial metalloproteases suggests that the eukaryotic metalloprotease genes arose as a consequence of ancient gene migration events that transferred these loci to the eukaryotic nucleus from the ancestral endosymbiotic organelle, followed by multiple duplication events.…”

The role of protein degradation in mitochondrial function and biogenesis

“…In addition, homo-multimerization of Yme1p was suggested by intragenic complementation between two yme1 alleles ( . Recently, a high-molecularweight complex containing Yme1p has been identified, as well as a complex involving both Afg3p and Rca1p (Arlt et al 1996;Thomas Langer, personal communication). Formation of homo-multimers is also seen with other members of the AAA family (Peters et al 1990(Peters et al , 1993Whiteheart et al 1994;Fröhlich et al 1995) and may be a common feature of these proteins.…”

Them-AAA Protease Processes CytochromecPeroxidase Preferentially at the Inner Boundary Membrane of Mitochondria

“…Central components of the proteolytic control system are two conserved AAA proteases that degrade misfolded or nonassembled inner membrane proteins: the i-AAA protease exposes its catalytic site to the intermembrane space (IMS), whereas the m-AAA protease is active at the matrix (for review see Juhola et al, 2000;Koppen and Langer, 2007). The m-AAA protease is a hetero-oligomeric complex composed of the homologous subunits AFG3L2 and paraplegin in humans (Atorino et al, 2003) and Yta10 (Afg3) and Yta12 (Rca1) in the budding yeast Saccharomyces cerevisiae (Arlt et al, 1996). Mutations in the m-AAA protease cause severe defects in various organisms, including respiratory deficiency in budding yeast (Arlt et al, 1998), accumulation of aberrant mitochondria in paraplegin-deficient mice (Ferreirinha et al, 2004) and neurodegeneration in humans (Nolden et al, 2005).…”