Synthesis, Processing and Assembly

Abstract

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⁾.