Family 3.A.8 - The Mitochondrial Protein Translocase Family
Family ID: 52653
The mitochondrial protein translocase (MPT), which brings nuclearly
encoded preproteins into mitochondria, is very complex with numerous
identified protein constituents that comprise three translocons,
one in the outer membrane (Tom40/70) and two in the inner membrane
(Tim17/23 and Tim22/54). These proteins include (1) several chaperone
proteins, (2) proteins of the outer membrane translocase (Tom)
import receptors, (3) proteins of the Tom channel complex, (4)
proteins of the two inner membrane translocases (Tim) and (5)
at least three "motor" proteins. Non-identical integral
membrane receptor proteins are called Tom70, Tom37, Tom22 and
Tom20. Of these receptor proteins, only Tom22 is essential for
protein import. The receptor delivers the substrate protein to
the outer membrane channel consisting of 5 hydrophobic proteins,
Tom40, Tom38, Tom7, Tom6 and Tom5. Tom40 is the core subunit of
this channel. It forms a b-stranded, cation-selective, high conductance
pore that specifically binds to and transports mitochondrial-targeting
peptides. The inner pore diameter has been estimated to be about
22 Å. The small Tom proteins may function in regulatory
capacities and are not essential.
The TOM complex
can apparently function independently of the two TIM complexes,
transporting proteins from the cytoplasm to the intermembrane
space. Conserved, intraprotein, hydrophilic targeting sequences,
different from matrix targeting sequences, are involved. Targeting
translocation across the outer membrane may be independent of
ATP and the pmf. About 30% of mitochondrial proteins lack matrix
targeting sequences. They are present in the outer membrane, the
intermembrane space and in the inner membrane. These proteins
may be imported via the TOM complex.
The two inner
membrane channel-forming complexes are both multicomponent. One
consists of at least 5 integral membrane Tim proteins: Tim33,
Tim23, Tim17, Tim14 and Tim11, as well as peripheral membrane
motor protein, Tim44. Tim23, possibly together with Tim17, exhibits
channel activity. Two chaperone proteins (mhsp70 and mGrpE) have
been suggested to function together with Tim44. Tim44 (with or
without the chaperone proteins) may function as an ATP-driven
import motor that pulls the precursor polypeptide chain through
the first Tim channel into the matrix. The second inner membrane
channel-forming complex consists of at least two integral membrane
proteins, Tim22 and Tim54. Integral inner membrane proteins may
first enter the matrix and then return to the inner membrane using
a second signal sequence exposed after the first has been removed.
Alternatively, inner membrane proteins may be directly targeted
in a pathway requiring intermembrane protein complexes as well
as the integral inner membrane Tim22/Tim54 complex. The Tom and
Tim proteins have homologues in yeast, fungi and/or animals. Tim23,
Tim17 and another S. cerevisiae protein, Tim22 (spQ12328), are
homologous to each other.
The second
import system depends on two water-soluble protein complexes that
are present in the intermembrane space. One contains the essential
Tim9 and Tim10 proteins and mediates transport of cytosolically
synthesized metabolite carrier proteins from the outer to the
inner membrane. The other complex includes the Tim8 and Tim13
proteins as well as associated Tim9 and mediates import of a subset
of integral inner membrane proteins. These two intermembrane complexes
deliver substrate proteins to two and possibly three different
inner membrane insertion sites, the Tim22-Tim54-Tim12 complex,
the Tim23-Tim44-Tim17-Tim11 complex and an uncharacterized complex.
Thus, multiple pathways are proposed for transfer of proteins
across the intermembrane space, for transfer across the inner
membrane, and for insertion into the inner membrane.
