F-U Hartl

G Attardi

H Murakami

HRB Pelham

J Ostermann

J Rassow

JE Rothman

K Verner

M Schleyer

M Schwaiger

MY Cheng

N Pfanner

RJ Deshaies

RJ Ellis

SK Randall

W-J Chen

WT Wickner

English

Crossref

Stress proteins and mitochondrial protein import

Pfanner, Nikolaus

Ostermann, Joachim

Rassow, Joachim

Hartl, Franz-Ulrich

Neupert, Walter

FreiDok plus

Universität München: Elektronischen Publikationen

Antonie van Leeuwenhoek 58: 191-193, 1990. 
9 1990 Kluwer Academic Publishers. Printed in the Netherlands. 
Stress proteins and mitoehondrial protein import 
Nikolaus Pfanner, Joachim Ostermann, Joachim Rassow, Franz-Ulrich Hartl & Walter Neupert 
Institut fiir Physiologische Chemie, Universitiit Miinchen, Goethestr. 33, D-8000 Miinchen 2, FRG 
Introduction 
Many proteins have to cross membranes to get 
from their site of synthesis, usually the cytosol, to 
their functional destination in various intracellular 
compartments (the organelles) (Wickner and 
Lodish, 1985). Recent research is directed towards 
elucidating the molecular mechanisms of transloca- 
tion of proteins across membranes that are 
naturally impermeable to macromolecules. We 
thereby have focused on the biogenesis of 
mitochondrial proteins. 
Mitochondria import the vast majority of their 
proteins from the cytosol (Attardi and Schatz, 
1988; Hartl and Neupert, 1990; Pfanner and 
Neupert, 1990). Precursor proteins are recognized 
by receptors on the mitochondrial surface and are 
imported at sites of close contact between outer 
and inner membranes. In the inner mitochondrial 
subcompartment, the matrix, the amino-terminal 
signal sequences (presequences) of the precursors 
are proteolytically removed by the enzyme process- 
ing peptidase. 
The process of membrane translocation of 
mitochondrial precursor proteins is not really un- 
derstood. We know that various energy sources, 
ATP in the cytosol and matrix and the electrical 
membrane potential across the inner membrane, 
are required. Moreover, precursor proteins are 
unfolded prior to translocation and are refolded in 
the matrix. Several stress proteins (heat shock 
proteins, hsps) seem to play critical roles with 
regard to translocation and modifying the confor- 
mation of precursor proteins. 
Translocation competence of mitochondrial 
precursor proteins 
The uptake of precursor proteins by mitochondria 
occurs predominantly in a posttranslational man- 
ner, i.e., fully synthesized precursor proteins are 
transported into the organelle. This implies that 
the precursor proteins in the cytosol have to adopt 
conformations which are compatible with the sub- 
sequent unfolding of the polypeptide chain, an es- 
sential prerequisite for membrane translocation. In 
particular, aggregation or misfolding of precursor 
proteins must be prevented. 
Upon the discovery that cytosolic heat shock 
proteins of 70 kd (ct-hsp70s) are involved in 
protein import (Deshaies et al., 1988; Murakami et 
al., 1988; Randall and Shore, 1989), it was 
generally assumed that ct-hsp70s participate in 
maintaining a translocation-competent confor- 
mation of precursor proteins. This is based on the 
observations that hsp70s seem to interact with 
(partially) unfolded proteins, thereby stabilizing a 
loosely folded conformation and preventing mis- 
folding or aggregation of proteins (Pelham, 1988; 
Rothman, 1989). The release of proteins from 
hsp70s requires hydrolysis of ATP. Indeed protein 
import into mitochondria was found to require 
ATP in the cytosol and the ATP-dependence could 
be correlated with the acquisition of transport-com- 
petence of the precursor proteins (Planner et al., 
1987, 1988; Verner and Schatz, 1987; Chen and 
Douglas, 1988). 
It has to be emphasized that cytosolic hsp70s 
and ATP are probably not directly involved in the 
unfolding of precursor proteins. We found that 
some precursor proteins with tightly, yet correctly 
folded domains did not require the addition of 
ATP for unfolding and membrane translocation, in 
contrast to the numerous precursor proteins with 
an intermediate degree of folded structure 
(Pfanner et al., 1990). As correctly folded domains 
obviously have a very low tendency for misfold- 
ing or aggregation, they may not depend on the 
protective effect of hsp70s. In molecular terms, 
tightly folded domains probably do not expose se- 
quences that would bind to hsp70s (Rothman, 
192 
1989), and thus there is no need for ATP to release 
hsp70s. It is concluded that ct-hsp70s stabilize the 
conformation of precursor proteins that would 
otherwise form improper interactions or structures 
in the cytosol. The actual unfolding of precursors 
may be performed by the membrane-bound import 
apparatus of mitochondria. 
Mitochondrial hsp70 and protein transport 
through contact sites 
Contact sites between outer and inner membranes 
are the main entry gate of mitochondria. This was 
demonstrated by the reversible arrest of precursor 
proteins in contact sites in a two-membrane span- 
ning manner (Schleyer and Neupert, 1985; 
Schwaiger et al., 1987). A recent study confirmed 
the implication that a polypeptide chain spanning 
two membranes is largely unfolded. Hybrid 
proteins with a tightly folded carboxyl-terminal 
domain and an amino-terminal portion of variable 
length were accumulated in mitochondrial contact 
sites such that the folded domain remained on the 
cytosolic side of the membranes. We thereby 
found that about 50 amino acid residues were suffi- 
cient to span both mitochondrial membranes 
(Rassow et al., 1990). Considering the distance 
across two protein-rich membranes, this result sug- 
gests that the polypeptide chain has to be rather 
extended. 
Where does the energy for an extensive unfold- 
ing of the polypeptide chain come from? The 
electrical potential across the inner membrane is 
required for the initial transfer of an amino-ter- 
minal portion of the precursor protein into the 
matrix. The completion of transport (including un- 
folding) of the major part of the precursor protein, 
however, can take place in the absence of the 
membrane potential (Schleyer and Neupert, 1985; 
Rassow et al., 1989). As discussed above, 
cytosolic ATP can also be excluded as the possible 
energy source. The precursor protein in transit 
through contact sites seems to interact with the 
mitochondrial hsp70 (mt-hsp70, also termed 
Ssclp) that is located in the matrix (Kang et al., 
1990). In a yeast mutant that was defective in mt- 
hsp70 in a temperature-sensitive manner, pre- 
cursor proteins could be inserted into contact sites 
such that the presequence reached the matrix 
space. However, the completion of transport, in- 
cluding the unfolding of the polypeptide chain on 
the cytosolic side, was impaired at the non-permis- 
sive temperature, suggesting that functional mt- 
hsp70 was necessary for unfolding and membrane 
translocation of the precursor protein. Indeed, the 
artificial unfolding of a precursor protein by a 
pretreatment with 7 M urea allowed a partial cir- 
cumvention of the transport defect in this mutant 
mitochondria (Kang et al., 1990). We propose a 
hypothesis in that one or more mt-hsp70s bind to 
precursor proteins emerging on the matrix side of 
the inner membrane and "pull" the precursor 
proteins towards the inside of mitochondria, 
thereby facilitating the unfolding reaction on the 
cytosolic side. The free energy of binding of a 
precursor protein to mt-hsp70 may thus provide 
the driving force for unfolding and vectorial trans- 
location of the polypeptide. ATP would then be 
indirectly required to allow release of the imported 
precursor protein from mt-hsp70, setting the heat 
shock protein free for new rounds of transport. 
Refolding of imported proteins 
Imported proteins do not refold spontaneously. 
Mt-hsp70 probably keeps them in an unfolded con- 
formation (Kang et al., 1990) and eventually trans- 
fers them to a heat shock protein of 60 kd in the 
matrix (hsp60). Hsp60 seems to act as "foldase", 
catalyzing the folding of polypeptides in an ATP- 
dependent process (Ostermann et al., 1989). At 
low levels of ATP, precursor proteins can be ac- 
cumulated on the surface of hsp60 in an unfolded 
conformation. Addition of ATP promotes the fol- 
ding of the polypeptide chain in association with 
hsp60. It is not known whether further com- 
ponents in the matrix participate in this folding 
reaction. The release of the proteins from hsp60 
requires additional protein factors and ATP 
(Ostermann et al., 1989). This function of hsp60 in 
folding imported proteins is an essential prerequi- 
site for the assembly of proteins into multi-subunit 
complexes as was found with a yeast mutant that 
was defective in hsp60 in a temperature-sensitive 
manner (Cheng et al., 1989). 
Conclusions and perspectives 
Stress proteins, cytosolic and mitochondrial 
193 
hsp70s and mitochondrial  hsp60, are important 
components  in the complex machinery that im- 
ports nuclear-encoded precursor proteins into 
mitochondria.  Hsp70s and hsp60 are involved in 
the various processes that involve modifying or 
stabilizing the conformation of  precursor proteins. 
The identification and characterization o f  these 
stress proteins should now allow a molecular  
analysis o f  the interaction with precursor proteins. 
Since the stress proteins o f  the hsp70- and hsp60- 
families are present in various intracellular com-  
partments,  they most  likely play critical roles in 
practically all processes that involve unfolding, 
translocation, folding or  assembly o f  newly syn- 
thesized proteins (for overview, see Ellis and Hem-  
mingsen,  1989; Rothman,  1989). Investigations on 
the role o f  stress proteins in mitochondrial  protein 
import  should thus reveal mechanisms that are 
most  likely o f  relevance for the biogenesis o f  
proteins and cell organelles in general. 
Acknowledgements 
We gratefully acknowledge the important contribu- 
tions o f  all our  colleagues, in particular Drs E. 
Craig, B. Guiard and A. Horwich,  to the work 
reviewed here. Studies o f  the authors '  laboratory 
were supported by the Deutsche Forschungs-  
gemeinschaft  (Sonderforschungsbereich 184) and 
the Fonds der Chemischen Industrie. 
References 
Attardi G, Schatz G (1988) Biogenesis of mitochondria. Annu 
Rev Cell Biol 4:289-333 
Chen W-J, Douglas MG (1988) An F1-ATPase 13-subunit 
precursor lacking an internal tetramer-forming domain is 
imported into mitochondria in the absence of ATP. J Biol 
Chem 263:4997-5000 
Cheng MY, Hartl F-U, Martin J, Pollock RA, Kalousek F, 
Neupert W, Hallberg EM, Hallberg RL, Horwich AL 
(1989) Mitochondrial heat-shock protein hsp60 is essential 
for assembly of proteins imported into yeast mitochondria. 
Nature 337:620-625 
Deshaies ILl, Koch BD, Wemer-Washbume M, Craig EA, 
Schekman R (1988) A subfamily of stress proteins 
facilitates translocation of secretory and mitochondrial 
precursor polypeptides. Nature 332:800-805 
Ellis 1LI, Hemmingsen SM (1989) Molecular chaperones: 
proteins essential for the biogenesis of some macro- 
molecular structures. Trends Biochem Sci 14:339-342 
Hartl F-U, Neupert W (1990) Protein sorting to mitochondria: 
evolutionary conservations of folding and assembly. 
Science 247:930-938 
Kang P-J, Ostermann J, Shilling J, Neupert W, Craig EA, Pfan- 
ner N (1990) Hsp70 in the mitochondrial matrix is required 
for translocation and folding of precursor proteins. Nature, 
in press 
Murakami H, Pain D, Blobel G (1988) 70-kD heat shock-re- 
lated protein is one of at least two distinct cytosolic factors 
stimulating protein import into mitochondria. J Cell Biol 
107:2051-2057 
Ostermann J, Horwich AL, Neupert W, Hartl F-U (1989) 
Protein folding in mitochondria requires complex formation 
with hsp60 and ATP hydrolysis. Nature 341:125-130 
Pelham HRB (1988) Heat shock proteins: coming in from the 
cold. Nature 332:776-777 
Pfanner N, Neupert W (1990) The mitochondrial protein im- 
port apparatus. Annu Rev Biochem 59:331-353 
Planner N, Tropschug M, Neupert W (1987) Mitochondrial 
protein import: nucleoside triphosphates are involved in 
conferring import-competence to precursors. Cell 49: 
815-823 
Pfanner N, Pfaller R, Kleene R, Ito M, Tropschug M, Neupert 
W (1988) Role of ATP in mitochondrial protein import: 
conformational alteration of a precursor protein can sub- 
stitute for ATP requirement. J Biol Chem 263:4049-4051 
Pfanner N, Rassow J, Guiard B, S611ner T, Hartl F-U, Neupert 
W (1990) Energy requirements for unfolding and 
membrane translocation of precursor proteins during import 
into mitochondria. J Biol Chem, in press 
Randall SK, Shore GC (1989) Import of a mutant 
mitochondrial precursor fails to respond to stimulation by a 
cytosolic factor. FEBS Lett 250:561-564 
Rassow J, Guiard B, Wienhues U, Herzog V, Hartl F-U, 
Neupert W (1989) Translocation arrest by reversible fol- 
ding of a precursor protein imported into mitochondria. A 
means to quantitate translocation contact sites. J Cell Biol 
109:1421-1428 
Rassow J, Hartl F-U, Guiard B, Pfanner N, Neupert W (1990) 
Protein segment in transit across the mitochondriai 
membranes. Submitted 
Rothman JE (1989) Polypeptide chain binding proteins: 
catalysts of protein folding and related processes in cells. 
Cell 59:591-601 
Schleyer M, Neupert W (1985) Transport of proteins into 
mitochondria: translocational intermediates spanning con- 
tact sites between outer and inner membranes. Cell 43: 
339-350 
Schwaiger M, Herzog V, Neupert W (1987) Characterization 
of translocation contact sites involved in the import of 
mitochondrial proteins. J Cell Biol 105:235-246 
Vemer K, Schatz G (1987) Import of an incompletely folded 
precursor protein into isolated mitochondria requires an 
energized inner membrane, but no added ATP. EMBO J 6: 
2449-2456 
Wickner WT, Lodish HF (1985) Multiple mechanisms of 
protein insertion into and across membranes. Science 230: 
400--407 


Open Access LMU ( Ludwig-Maximilians-Univ. München)

Antonie van Leeuwenhoek 58: 191-193, 1990. 9 1990 Kluwer Academic Publishers. Printed in the Netherlands. Stress proteins and mitoehondrial protein import Nikolaus Pfanner, Joachim Ostermann, Joachim Rassow, Franz-Ulrich Hartl & Walter Neupert Institut fiir Physiologische Chemie, Universitiit Miinchen, Goethestr. 33, D-8000 Miinchen 2, FRG Introduction Many proteins have to cross membranes to get from their site of synthesis, usually the cytosol, to their functional destination i various intracellular compartments (the organelles) (Wickner and Lodish, 1985). Recent research is directed towards elucidating the molecular mechanisms oftransloca- tion of proteins across membranes that are naturally impermeable to macromolecules. We thereby have focused on the biogenesis of mitochondrial proteins. Mitochondria import the vast majority of their proteins from the cytosol (Attardi and Schatz, 1988; Hartl and Neupert, 1990; Pfanner and Neupert, 1990). Precursor proteins are recognized by receptors on the mitochondrial surface and are imported at sites of close contact between outer and inner membranes. In the inner mitochondrial subcompartment, the matrix, the amino-terminal signal sequences (presequences) of the precursors are proteolytically removed by the enzyme process- ing peptidase. The process of membrane translocation of mitochondrial precursor proteins is not really un- derstood. We know that various energy sources, ATP in the cytosol and matrix and the electrical membrane potential across the inner membrane, are required. Moreover, precursor proteins are unfolded prior to translocation and are refolded in the matrix. Several stress proteins (heat shock proteins, hsps) seem to play critical roles with regard to translocation and modifying the confor- mation of precursor proteins. Translocation competence of mitochondrial precursor proteins The uptake of precursor proteins by mitochondria occurs predominantly in a posttranslational man- ner, i.e., fully synthesized precursor proteins are transported into the organelle. This implies that the precursor proteins in the cytosol have to adopt conformations which are compatible with the sub- sequent unfolding of the polypeptide chain, an es- sential prerequisite for membrane translocation. In particular, aggregation or misfolding of precursor proteins must be prevented. Upon the discovery that cytosolic heat shock proteins of 70 kd (ct-hsp70s) are involved in protein import (Deshaies et al., 1988; Murakami et al., 1988; Randall and Shore, 1989), it was generally assumed that ct-hsp70s participate in maintaining a translocation-competent confor- mation of precursor proteins. This is based on the observations that hsp70s seem to interact with (partially) unfolded proteins, thereby stabilizing a loosely folded conformation and preventing mis- folding or aggregation of proteins (Pelham, 1988; Rothman, 1989). The release of proteins from hsp70s requires hydrolysis of ATP. Indeed protein import into mitochondria was found to require ATP in the cytosol and the ATP-dependence ould be correlated with the acquisition of transport-com- petence of the precursor proteins (Planner et al., 1987, 1988; Verner and Schatz, 1987; Chen and Douglas, 1988). It has to be emphasized that cytosolic hsp70s and ATP are probably not directly involved in the unfolding of precursor proteins. We found that some precursor proteins with tightly, yet correctly folded domains did not require the addition of ATP for unfolding and membrane translocation, i  contrast to the numerous precursor proteins with an intermediate degree of folded structure (Pfanner et al., 1990). As correctly folded domains obviously have a very low tendency for misfold- ing or aggregation, they may not depend on the protective ffect of hsp70s. In molecular terms, tightly folded domains probably do not expose se- quences that would bind to hsp70s (Rothman, 192 1989), and thus there is no need for ATP to release hsp70s. It is concluded that ct-hsp70s tabilize the conformation of precursor proteins that would otherwise form improper interactions or structures in the cytosol. The actual unfolding of precursors may be performed by the membrane-bound import apparatus of mitochondria. Mitochondrial hsp70 and protein transport through contact sites Contact sites between outer and inner membranes are the main entry gate of mitochondria. This was demonstrated by the reversible arrest of precursor proteins in contact sites in a two-membrane span- ning manner (Schleyer and Neupert, 1985; Schwaiger et al., 1987). A recent study confirmed the implication that a polypeptide chain spanning two membranes is largely unfolded. Hybrid proteins with a tightly folded carboxyl-terminal domain and an amino-terminal portion of variable length were accumulated in mitochondrial contact sites such that the folded domain remained on the cytosolic side of the membranes. We thereby found that about 50 amino acid residues were suffi- cient to span both mitochondrial membranes (Rassow et al., 1990). Considering the distance across two protein-rich membranes, this result sug- gests that the polypeptide chain has to be rather extended. Where does the energy for an extensive unfold- ing of the polypeptide chain come from? The electrical potential across the inner membrane is required for the initial transfer of an amino-ter- minal portion of the precursor protein into the matrix. The completion of transport (including un- folding) of the major part of the precursor protein, however, can take place in the absence of the membrane potential (Schleyer and Neupert, 1985; Rassow et al., 1989). As discussed above, cytosolic ATP can also be excluded as the possible energy source. The precursor protein in transit through contact sites seems to interact with the mitochondrial hsp70 (mt-hsp70, also termed Ssclp) that is located in the matrix (Kang et al., 1990). In a yeast mutant hat was defective in mt- hsp70 in a temperature-sensitive manner, pre- cursor proteins could be inserted into contact sites such that the presequence reached the matrix space. However, the completion of transport, in- cluding the unfolding of the polypeptide chain on the cytosolic side, was impaired at the non-permis- sive temperature, suggesting that functional mt- hsp70 was necessary for unfolding and membrane translocation of the precursor protein. Indeed, the artificial unfolding of a precursor protein by a pretreatment with 7 M urea allowed a partial cir- cumvention of the transport defect in this mutant mitochondria (Kang et al., 1990). We propose a hypothesis in that one or more mt-hsp70s bind to precursor proteins emerging on the matrix side of the inner membrane and "pull" the precursor proteins towards the inside of mitochondria, thereby facilitating the unfolding reaction on the cytosolic side. The free energy of binding of a precursor protein to mt-hsp70 may thus provide the driving force for unfolding and vectorial trans- location of the polypeptide. ATP would then be indirectly required to allow release of the imported precursor protein from mt-hsp70, setting the heat shock protein free for new rounds of transport. Refolding of imported proteins Imported proteins do not refold spontaneously. Mt-hsp70 probably keeps them in an unfolded con- formation (Kang et al., 1990) and eventually trans- fers them to a heat shock protein of 60 kd in the matrix (hsp60). Hsp60 seems to act as "foldase", catalyzing the folding of polypeptides in an ATP- dependent process (Ostermann et al., 1989). At low levels of ATP, precursor proteins can be ac- cumulated on the surface of hsp60 in an unfolded conformation. Addition of ATP promotes the fol- ding of the polypeptide chain in association with hsp60. It is not known whether further com- ponents in the matrix participate in this folding reaction. The release of the proteins from hsp60 requires additional protein factors and ATP (Ostermann et al., 1989). This function of hsp60 in folding imported proteins is an essential prerequi- site for the assembly of proteins into multi-subunit complexes as was found with a yeast mutant hat was defective in hsp60 in a temperature-sensitive manner (Cheng et al., 1989). Conclusions and perspectives Stress proteins, cytosolic and mitochondrial 193 hsp70s and mitochondrial hsp60, are important components in the complex machinery that im- ports nuclear-encoded precursor proteins into mitochondria. Hsp70s and hsp60 are involved in the various processes that involve modifying or stabilizing the conformation of  precursor proteins. The identification and characterization f  these stress proteins should now allow a molecular analysis of  the interaction with precursor proteins. Since the stress proteins of  the hsp70- and hsp60- families are present in various intracellular com- partments, they most likely play critical roles in practically all processes that involve unfolding, translocation, folding or assembly of  newly syn- thesized proteins (for overview, see Ellis and Hem- mingsen, 1989; Rothman, 1989). Investigations on the role of  stress proteins in mitochondrial protein import should thus reveal mechanisms that are most likely of  relevance for the biogenesis of  proteins and cell organelles in general. Acknowledgements We gratefully acknowledge the important contribu- tions o f  all our colleagues, in particular Drs E. Craig, B. Guiard and A. Horwich, to the work reviewed here. Studies of  the authors' laboratory were supported by the Deutsche Forschungs- gemeinschaft (Sonderforschungsbereich 184) and the Fonds der Chemischen Industrie. References Attardi G, Schatz G (1988) Biogenesis of mitochondria. Annu Rev Cell Biol 4:289-333 Chen W-J, Douglas MG (1988) An F1-ATPase 13-subunit precursor lacking an internal tetramer-forming domain is imported into mitochondria in the absence of ATP. J Biol Chem 263:4997-5000 Cheng MY, Hartl F-U, Martin J, Pollock RA, Kalousek F, Neupert W, Hallberg EM, Hallberg RL, Horwich AL (1989) Mitochondrial heat-shock protein hsp60 is essential for assembly of proteins imported into yeast mitochondria. Nature 337:620-625 Deshaies ILl, Koch BD, Wemer-Washbume M, Craig EA, Schekman R (1988) A subfamily of stress proteins facilitates translocation of secretory and mitochondrial precursor polypeptides. Nature 332:800-805 Ellis 1LI, Hemmingsen SM (1989) Molecular chaperones: proteins essential for the biogenesis of some macro- molecular structures. Trends Biochem Sci 14:339-342 Hartl F-U, Neupert W (1990) Protein sorting to mitochondria: evolutionary conservations f folding and assembly. Science 247:930-938 Kang P-J, Ostermann J, Shilling J, Neupert W, C aig EA, Pfan- ner N (1990) Hsp70 in the mitochondrial matrix is required for translocation and folding of precursor proteins. Nature, in press Murakami H, Pain D, Blobel G (1988) 70-kD heat shock-re- lated protein is one of at least two distinct cytosolic factors stimulating protein import into mitochondria. J Cell Biol 107:2051-2057 Ostermann J, Horwich AL, Neupert W, Hartl F-U (1989) Protein folding in mitochondria requires complex formation with hsp60 and ATP hydrolysis. Nature 341:125-130 Pelham HRB (1988) Heat shock proteins: coming in from the cold. Nature 332:776-777 Pfanner N, Neupert W (1990) The mitochondrial protein im- port apparatus. Annu RevBiochem 59:331-353 Planner N, Tropschug M, Neupert W (1987) Mitochondrial protein import: nucleoside triphosphates are involved in conferring import-competence to precursors. Cell 49: 815-823 Pfanner N, Pfaller R, Kleene R, Ito M, Tropschug M, Neupert W (1988) Role of ATP in mitochondrial protein import: conformational alteration of a precursor protein can sub- stitute for ATP requirement. J Biol Chem 263:4049-4051 Pfanner N, Rassow J, Guiard B, S611ner T, Hartl F-U, Neupert W (1990) Energy requirements for unfolding and membrane translocation of precursor proteins during import into mitochondria. J Biol Chem, in press Randall SK, Shore GC (1989) Import of a mutant mitochondrial precursor fails to re pond to stimulation by a cytosolic factor. FEBS Lett 250:561-564 Rassow J, Guiard B, Wienhues U, Herzog V, Hartl F-U, Neupert W (1989) Translocation arrest by versible fol- ding of a precursor protein imported into mitochondria. A means to quantitate translocation contact sites. J Cell Biol 109:1421-1428 Rassow J, Hartl F-U, Guiard B, Pfanner N, Neupert W (1990) Protein segment in transit across the mitochondriai membranes. Submitted Rothman JE (1989) Polypeptide chain binding proteins: catalysts of protein folding and related processes in cells. Cell 59:591-601 Schleyer M, Neupert W (1985) Transport of proteins into mitochondria: translocational intermediates spanning con- tact sites between outer and inner membranes. Cell 43:339-350 Schwaiger M, Herzog V, Neupert W (1987) Characterization of translocation contact sites involved in the import of mitochondrial proteins. J Cell Biol 105:235-246 Vemer K, Schatz G (1987) Import of an incompletely folded precursor protein into isolated mitochondria requires an energized inner membrane, but no added ATP. EMBO J 6: 2449-2456 Wickner WT, Lodish HF (1985) Multiple mechanisms of protein insertion into and across membranes. Science 230: 400--407 

Biogenesis of mitochondria.

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Stress proteins and mitochondrial protein import

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