Functions of outer membrane receptors in mitochondrial protein import.

Most mitochondrial proteins are synthesized in the cytosol as precursor proteins and are imported into mitochondria. The targeting signals for mitochondria are encoded in the presequences or in the mature parts of the precursor proteins, and are decoded by the receptor sites in the translocator complex in the mitochondrial outer membrane. The recently determined NMR structure of the general import receptor Tom20 in a complex with a presequence peptide reveals that, although the amphiphilicity and positive charges of the presequence is essential for the import ability of the presequence, Tom20 recognizes only the amphiphilicity, but not the positive charges. This leads to a new model that different features associated with the mitochondrial targeting sequence of the precursor protein can be recognized by the mitochondrial protein import system in different steps during the import.

[1]  D. Gorenstein,et al.  2D NMR and structural model for a mitochondrial signal peptide bound to a micelle. , 1990, Biochemistry.

[2]  K. Mihara,et al.  Interaction of mitochondrial targeting signals with acidic receptor domains along the protein import pathway: evidence for the ‘acid chain’ hypothesis , 1998, The EMBO journal.

[3]  K. Mihara,et al.  Protein Import into Mammalian Mitochondria , 1996, The Journal of Biological Chemistry.

[4]  K. Iwata,et al.  Interaction between mitochondrial precursor proteins and cytosolic soluble domains of mitochondrial import receptors, Tom20 and Tom70, measured by surface plasmon resonance. , 1998, Biochemical and biophysical research communications.

[5]  J. Richards,et al.  A chemically synthesized pre‐sequence of an imported mitochondrial protein can form an amphiphilic helix and perturb natural and artificial phospholipid bilayers. , 1986, The EMBO journal.

[6]  W. Neupert,et al.  cis and trans Sites of the TOM Complex of Mitochondria in Unfolding and Initial Translocation of Preproteins* , 1998, The Journal of Biological Chemistry.

[7]  T. Lithgow,et al.  The protein import receptor of mitochondria. , 1995, Trends in biochemical sciences.

[8]  N. Nomura,et al.  Analysis of the Functional Domain of the Rat Liver Mitochondrial Import Receptor Tom20* , 1997, The Journal of Biological Chemistry.

[9]  N. Pfanner,et al.  The intermembrane space domain of mitochondrial Tom22 functions as a trans binding site for preproteins with N-terminal targeting sequences , 1997, Molecular and cellular biology.

[10]  R. Benz,et al.  The Preprotein Translocation Channel of the Outer Membrane of Mitochondria , 1998, Cell.

[11]  W. Neupert,et al.  Tom71, a Novel Homologue of the Mitochondrial Preprotein Receptor Tom70* , 1996, The Journal of Biological Chemistry.

[12]  H. McBride,et al.  A signal-anchor sequence selective for the mitochondrial outer membrane , 1992, The Journal of cell biology.

[13]  N. Nomura,et al.  A human homolog of the mitochondrial protein import receptor Mom19 can assemble with the yeast mitochondrial receptor complex , 1995, FEBS letters.

[14]  S. Merchant,et al.  How membrane proteins travel across the mitochondrial intermembrane space. , 1999, Trends in biochemical sciences.

[15]  R. Jensen,et al.  Tim23p contains separate and distinct signals for targeting to mitochondria and insertion into the inner membrane. , 1998, Molecular biology of the cell.

[16]  F. Palmieri.  Mitochondrial carrier proteins , 1994, FEBS letters.

[17]  W. Neupert,et al.  Internal targeting signal of the BCS1 protein: a novel mechanism of import into mitochondria. , 1996, The EMBO journal.

[18]  M. Bauer,et al.  Protein translocation into mitochondria: the role of TIM complexes. , 2000, Trends in cell biology.

[19]  H. Matsubara,et al.  Precise determination of the mitochondrial import signal contained in a 70 kDa protein of yeast mitochondrial outer membrane. , 1989, Journal of biochemistry.

[20]  W. Neupert,et al.  A crucial role of the mitochondrial protein import receptor MOM19 for the biogenesis of mitochondria , 1994, The Journal of cell biology.

[21]  W. Neupert,et al.  Transport of the ADP/ATP carrier of mitochondria from the TOM complex to the TIM22·54 complex , 1999, The EMBO journal.

[22]  J. Turnbull,et al.  Characterization of the N-terminal targeting signal binding domain of the mitochondrial outer membrane receptor, Tom20. , 1998, Biochemistry.

[23]  N. Pfanner,et al.  Import of Carrier Proteins into Mitochondria , 1999, Biological chemistry.

[24]  Reiner Hegerl,et al.  Tom40, the Pore-Forming Component of the Protein-Conducting Tom Channel in the Outer Membrane of Mitochondria , 2001, The Journal of cell biology.

[25]  E. Craig,et al.  Mitochondrial preprotein translocase. , 1997, Annual review of cell and developmental biology.

[26]  T. Lithgow,et al.  Reconstitution of the initial steps of mitochondrial protein import , 1995, Nature.

[27]  W. Neupert,et al.  Specific recognition of mitochondrial preproteins by the cytosolic domain of the import receptor MOM72. , 1994, The Journal of biological chemistry.

[28]  Walter Neupert.  Protein import into mitochondria. , 1997 .

[29]  W. Neupert,et al.  Role of the N‐ and C‐termini of porin in import into the outer membrane of Neurospora mitochondria , 1996, FEBS letters.

[30]  M. Bauer,et al.  Biogenesis of Tim23 and Tim17, integral components of the TIM machinery for matrix‐targeted preproteins , 1998, The EMBO journal.

[31]  M. Mori,et al.  Characterization of the novel mitochondrial protein import component, Tom34, in mammalian cells. , 1999, Journal of biochemistry.

[32]  L. Gierasch,et al.  Exploring the conformational roles of signal sequences: synthesis and conformational analysis of lambda receptor protein wild-type and mutant signal peptides. , 1984, Biochemistry.

[33]  H. Horstmann,et al.  Protein import into yeast mitochondria is accelerated by the outer membrane protein MAS70. , 1990, The EMBO journal.

[34]  E. Schleiff,et al.  Interactions of the Human Mitochondrial Protein Import Receptor, hTom20, with Precursor Proteins in Vitro Reveal Pleiotropic Specificities and Different Receptor Domain Requirements* , 1997, The Journal of Biological Chemistry.

[35]  T. Lithgow,et al.  Mas37p, a novel receptor subunit for protein import into mitochondria , 1995, The Journal of cell biology.

[36]  W. Neupert,et al.  Biogenesis of Tom40, Core Component of the Tom Complex of Mitochondria , 1999, The Journal of cell biology.

[37]  T. Ikenoue,et al.  Charged Amino Acids at the Carboxyl-Terminal Portions Determine the Intracellular Locations of Two Isoforms of Cytochromeb 5 * , 1998, The Journal of Biological Chemistry.

[38]  H. Riezman,et al.  Import of proteins into mitochondria: nucleotide sequence of the gene for a 70‐kd protein of the yeast mitochondrial outer membrane. , 1983, The EMBO journal.

[39]  B. Dobberstein,et al.  Common Principles of Protein Translocation Across Membranes , 1996, Science.

[40]  K. Mihara,et al.  Characterization of the Signal That Directs Tom20 to the Mitochondrial Outer Membrane , 2000, The Journal of cell biology.

[41]  A. Valencia,et al.  Identification of a Mammalian Homologue of the Fungal Tom70 Mitochondrial Precursor Protein Import Receptor as a Thyroid Mitochondrial Precursor Protein Import Receptor as a Thyroid Hormone‐Regulated Gene in Specific Brain Regions , 1999, Journal of neurochemistry.

[42]  M. Kiebler,et al.  Import of ADP/ATP carrier into mitochondria: two receptors act in parallel , 1990, The Journal of cell biology.

[43]  J. Richards,et al.  Amphiphilicity is essential for mitochondrial presequence function. , 1988, The EMBO journal.

[44]  V. Hines,et al.  Precursor binding to yeast mitochondria. A general role for the outer membrane protein Mas70p. , 1993, The Journal of biological chemistry.

[45]  G. Shore,et al.  Identification of the human mitochondrial protein import receptor, huMas20p. Complementation of Δmas20 in yeast , 1995, FEBS letters.

[46]  N. Pfanner,et al.  Functional Staging of ADP/ATP Carrier Translocation across the Outer Mitochondrial Membrane* , 1999, The Journal of Biological Chemistry.

[47]  N. Pfanner,et al.  Versatility of the mitochondrial protein import machinery , 2001, Nature Reviews Molecular Cell Biology.

[48]  D. Kohda,et al.  NMR identification of the Tom20 binding segment in mitochondrial presequences. , 2001, Journal of molecular biology.

[49]  K. Mihara,et al.  Cytoplasmic chaperones determine the targeting pathway of precursor proteins to mitochondria. , 1996, The EMBO journal.

[50]  T. Tanaka,et al.  Conformational requirement of signal sequences functioning in yeast: circular dichroism and 1H nuclear magnetic resonance studies of synthetic peptides. , 1990, Biochemistry.

[51]  K. Dietmeier,et al.  Tom5 functionally links mitochondrial preprotein receptors to the general import pore , 1997, Nature.

[52]  D. S. Allison,et al.  Artificial mitochondrial presequences. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[53]  W. Neupert,et al.  Mechanisms of protein import across the mitochondrial outer membrane. , 1996, Trends in cell biology.

[54]  N. Pfanner,et al.  The cleavable presequence is not essential for import and assembly of the phosphate carrier of mammalian mitochondria but enhances the specificity and efficiency of import. , 1992, The Journal of biological chemistry.

[55]  W. Neupert,et al.  An Import Signal in the Cytosolic Domain of theNeurospora Mitochondrial Outer Membrane Protein TOM22* , 1998, The Journal of Biological Chemistry.

[56]  J. Schneider-Mergener,et al.  Distribution of Binding Sequences for the Mitochondrial Import Receptors Tom20, Tom22, and Tom70 in a Presequence-carrying Preprotein and a Non-cleavable Preprotein* , 1999, The Journal of Biological Chemistry.

[57]  M. Nakai,et al.  Identification of yeast MAS17 encoding the functional counterpart of the mitochondrial receptor complex protein MOM22 of Neurospora crassa. , 1995, FEBS letters.

[58]  M. Douglas,et al.  Mitochondrial import of the ADP/ATP carrier protein in Saccharomyces cerevisiae. Sequences required for receptor binding and membrane translocation. , 1988, The Journal of biological chemistry.

[59]  K. Dietmeier,et al.  Tom40 forms the hydrophilic channel of the mitochondrial import pore for preproteins , 1998, Nature.

[60]  S. Nuttall,et al.  A receptor for the import of proteins into human mitochondria. , 1996, European journal of biochemistry.

[61]  S. Nuttall,et al.  hTom34: a novel translocase for the import of proteins into human mitochondria. , 1997, DNA and cell biology.

[62]  G. Heijne.  Mitochondrial targeting sequences may form amphiphilic helices. , 1986 .

[63]  N. Pfanner,et al.  The three modules of ADP/ATP carrier cooperate in receptor recruitment and translocation into mitochondria , 2001, The EMBO journal.

[64]  N. Pfanner.  Protein sorting: Recognizing mitochondrial presequences , 2000, Current Biology.

[65]  K. Dietmeier,et al.  Identification of a third yeast mitochondrial Tom protein with tetratrico peptide repeats , 1996, FEBS letters.

[66]  N. Pfanner,et al.  Mitochondrial protein import. , 1989, Biochimica et biophysica acta.

[67]  K. Mihara,et al.  A mitochondrial import factor purified from rat liver cytosol is an ATP‐dependent conformational modulator for precursor proteins. , 1993, The EMBO journal.

[68]  R. Hegerl,et al.  The Tom Core Complex , 1999, The Journal of cell biology.

[69]  N. Pfanner,et al.  Multistep assembly of the protein import channel of the mitochondrial outer membrane , 2001, Nature Structural Biology.

[70]  W. Neupert,et al.  Mitochondrial Protein Import , 1997, The Journal of Biological Chemistry.

[71]  G. Schulz,et al.  The mitochondrial import receptor Tom70: identification of a 25 kDa core domain with a specific binding site for preproteins. , 2000, Journal of molecular biology.

[72]  E. Mekada,et al.  Characterization of Rat TOM40, a Central Component of the Preprotein Translocase of the Mitochondrial Outer Membrane* , 2000, The Journal of Biological Chemistry.

[73]  M. Mori,et al.  Identification and Functional Analysis of Human Tom22 for Protein Import into Mitochondria , 2000, Molecular and Cellular Biology.

[74]  R. Hodges,et al.  and R into mitochondria . preprotein receptor Tom 22 in protein import Role of the intermembrane-space domain of the , 1996 .

[75]  W. Neupert,et al.  MOM22 is a receptor for mitochondrial targeting sequences and cooperates with MOM19. , 1995, The EMBO journal.

[76]  M. Ryan,et al.  Functional analysis of human metaxin in mitochondrial protein import in cultured cells and its relationship with the Tom complex. , 2000, Biochemical and biophysical research communications.

[77]  T. Lithgow,et al.  The mitochondrial outer membrane protein Mas22p is essential for protein import and viability of yeast. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[78]  T. Lithgow,et al.  Functional cooperation of mitochondrial protein import receptors in yeast. , 1993, The EMBO journal.

[79]  W. Neupert,et al.  Assembly of Tom6 and Tom7 into the TOM Core Complex ofNeurospora crassa * , 2001, The Journal of Biological Chemistry.

[80]  M. Kiebler,et al.  The mitochondrial receptor complex: A central role of MOM22 in mediating preprotein transfer from receptors to the general insertion pore , 1993, Cell.

[81]  N. Pfanner,et al.  Mechanisms of protein translocation into mitochondria. , 1999, Biochimica et biophysica acta.

[82]  P. Schultz,et al.  Uncoupling of transfer of the presequence and unfolding of the mature domain in precursor translocation across the mitochondrial outer membrane. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[83]  B. Guiard,et al.  An internal targeting signal directing proteins into the mitochondrial intermembrane space. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[84]  W. Neupert,et al.  MOM19, an import receptor for mitochondrial precursor proteins , 1989, Cell.

[85]  N. Pfanner,et al.  The protein import receptor MOM19 of yeast mitochondria , 1993, FEBS letters.

[86]  P. Bornstein,et al.  Metaxin Is a Component of a Preprotein Import Complex in the Outer Membrane of the Mammalian Mitochondrion* , 1997, The Journal of Biological Chemistry.

[87]  I. Shimada,et al.  N-terminal half of a mitochondrial presequence peptide takes a helical conformation when bound to dodecylphosphocholine micelles: a proton nuclear magnetic resonance study. , 1989, Journal of biochemistry.

[88]  T. Lithgow,et al.  The Yeast Mitochondrial Protein Import Receptor Mas20p Binds Precursor Proteins through Electrostatic Interaction with the Positively Charged Presequence (*) , 1995, The Journal of Biological Chemistry.

[89]  W. Neupert,et al.  Mitochondrial protein import: Reversible binding of the presequence at the trans side of the outer membrane drives partial translocation and unfolding , 1995, Cell.

[90]  L. Gierasch,et al.  Molecular mechanisms of protein secretion: the role of the signal sequence. , 1986, Advances in protein chemistry.

[91]  K. Dietmeier,et al.  Differential Recognition of Preproteins by the Purified Cytosolic Domains of the Mitochondrial Import Receptors Tom20, Tom22, and Tom70* , 1997, The Journal of Biological Chemistry.

[92]  D. Kohda,et al.  Structural Basis of Presequence Recognition by the Mitochondrial Protein Import Receptor Tom20 , 2000, Cell.

[93]  N. Pfanner,et al.  Preprotein Translocase of the Outer Mitochondrial Membrane: Molecular Dissection and Assembly of the General Import Pore Complex , 1998, Molecular and Cellular Biology.

[94]  W. Neupert,et al.  Structural requirements of Tom40 for assembly into preexisting TOM complexes of mitochondria. , 2001, Molecular biology of the cell.

[95]  R. Stroud,et al.  Crystal Structure of the Signal Sequence Binding Subunit of the Signal Recognition Particle , 1998, Cell.

[96]  K. Mihara.  Targeting and insertion of nuclear‐encoded preproteins into the mitochondrial outer membrane , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[97]  E. Mekada,et al.  Identification of Mammalian TOM22 as a Subunit of the Preprotein Translocase of the Mitochondrial Outer Membrane* , 2000, The Journal of Biological Chemistry.

[98]  H. Weiner,et al.  Structure of the cytosolic domain of TOM5, a mitochondrial import protein , 2000, FEBS letters.