Synthesis, Processing and Assembly

OTC protein is synthesized on free polysomes from its mRNA in the liver cytosoly(52) resulting in a 32 amino acid leader peptide and a 322 amino acid subunit called pOTC(6,53,54). As the nascent peptide of pOTC is released from the ribosome, it associates with several different molecular chaperones which bind the precursor and prevent its aggregation or irreversible folding. These include a heterodimeric protein termed mitochondrial import stimulating factor (MSF)(55,56), a constitutive heat shock cognate 70 protein (hsc70)(57), a human homolog of bacterial heat shock protein DnaJ called HSDJ which is farnesylated to become active(58) and a presequence binding factor (PBF)(59). This pOTC-chaperone complex acts as a transport particle and moves to the mitochondria, possibly along microtubules. MSF cleaves ATP and delivers pOTC to a group of Tom subunits (transport across the outer membrane) at translocation contact sites where the outer and inner mitochondrial membranes are in apposition(56,63) Polyamines may play a role in binding of pOTC to the outer membrane (61,62). The import receptor for pOTC-MSF is a Tom70-Tom37 complex and is transferred to Tom22-Tom20 subunits where it enters a protein channel made up of Tom subunits 40,38,7,6 and 5(56,63). A Tom34 may be a novel translocase in human mitochondria(64).