La existencia de las proteínas comienza como una cadena lineal de aa, enseguida y
durante la síntesis, estos polipéptidos deben plegarse para adoptar sus
configuraciones nativas. Cambios modestos en el ambiente de las proteínas pueden
afectar su función.



The renaturation pathway of BPTI showing the conformations of its polypeptide
backbone as deduced from disulfide trapping experiments and NMR measurements.
(note that these views of the protein differ from the picture by a slight rotation about
the vertical axis). The fully reduced and native proteins are represented by R and N,
respectively. The sequence numbers of the Cys residues involved in each disulfide
bond are given in parentheses below the diagram representing each folding
intermediate, Ia and IB, are in rapid equilibrium. the “+” between intermediates IIA
and IIB indicates that both are formed directly from the one-disulfide intermediates,
intermediates
that both convert directly to the NSH2, and that either or both are intermediates in
the rearrangement of IIC to NSH2.


The classical Hsp70 mechanism based on prevention of aggregation. In this
mechanism, the Hsp70 prevents aggregation of the unfolded protein, thus providing
the protein with the opportunity to refold itself into its native form, or to
spontaneously and irreversibly aggregate. (i) The unfolded ‘client’ polypeptide
(pink) with exposed hydrophobic residues (brown patches) is recognized and first
bound by Hsp40 (yellow, with J representing the J-domain). (ii) ATP–Hsp70 (black)
weakly binds to the client near Hsp40. (iii) The J-domain of Hsp40 triggers ATP
hydrolysis and Hsp70 ‘locking’
locking (grey) on the client,
client preventing its aggregation
aggregation.
Hsp40 then dissociates. (iv) NEF accelerates the release of ADP, and the unlocking
and dissociation of Hsp70 from the unchanged client. This is then followed by
either (v) spontaneous native folding or (vi) irreversible aggregation. Alternatively,
the unfolded protein is once again bound by Hsp40 and Hsp70 and undergoes
another ATP-fuelled cycle of binding, locking and release



The catalysis of protein refolding. As indicated, a misfolded protein is initially
captured by hydrophobic interactions along one rim of the barrel. The subsequent
binding of ATP plus a protein cap increases the diameter of the barrel rim, which
may transiently stretch (partly unfold) the client protein. This also confines the
protein in an enclosed space, where it has a new opportunity to fold. After about 15
seconds, ATP hydrolysis ejects the protein, whether folded or not, and the cycle
repeats. This type of molecular chaperone is also known as a chaperonin; it is
designated as hsp60 in mitochondria
mitochondria, TCP-1 in the cytosol of vertebrate cells,
cells and
GroEL in bacteria. As indicated, only half of the symmetrical barrel operates on a
client protein at any one time. (B) The structure of GroEL bound to its GroES cap,
as determined by x-ray crystallography. On the left is shown the outside of the
barrel-like structure and on the right a cross section through its center. (B, adapted
from B. Bukace and A.L. Horwich, Cell 92:351–366, 1998.)














Ubiquitin is a highly conserved, 76-residue (8.5 kDa) polypeptide widespread in
eukaryotes. The amino acid sequences of yeast and human are 53% identical.
Proteins are condemned to degradation through ligation to ubiquitin.



EI- unida a ubiquitina.se transfiere a E2, E3 es la ligasa de ubiquitina que selecciona
el sustrato




The structure of the 20S proteasome (yeast) has been resolved recently ( Groll M,
Ditzel L, Lowe, J, Stock D, Bochtler M, Bartunik, HD. & Huber, R 1997 Nature
386:463--471) The active site residues are located in the subunits beta 1, 2 and 5.
The active site trias consists of the residues Thr1, Lys33 and Ser129.







Step 3: As SRP and its receptor dissociate from the nascent chain, accompanied by
hydrolysis of GTP, Step 4: The polypeptide chain elongates; then the signal
sequence is cleaved by a signal peptidase in the ER lumen and is rapidly degraded.
tep 5: The peptide chain continues to elongate and is extruded into the ER lumen
through the translocon. tep 6: The peptide chain continues to elongate until
translation is completed.


a | Preprotein or membrane protein synthesis starts on a free ribosome in the cytosol.
The signal-recognition particle (SRP) complex binds to the signal or signal-anchor
sequence, which is exposed from the ribosome tunnel exit after approximately 70
amino acids have been synthesized. b | The ribosome nascent chain–SRP complex is
subsequently targeted to the protein-conducting channel (PCC) of the Sec
translocase by the membrane bound receptor FtsY (or SR in mammals). c | The
SRP–FtsY interaction increases the GTP-binding affinity of both proteins, and
subsequent GTP binding releases the signal sequence from its association with the
SRP, after which the large subunit of the ribosome docks onto the PCC. The signal
or signal-anchor sequence opens the PCC in conjunction with the ribosome and
initiates the translocation or membrane insertion event. d | Hydrolysis of GTP
dissociates the SRP–FtsY complex and recycles the SRP into the cytosol for another
round of ribosome membrane targeting.




Precursor proteins (brown) with positively charged amino-terminal presequences, -barrel
outer-membrane
t b proteins
t i (dark
(d k green),) andd multispanning
lti i inner-membrane
i b proteins
t i (blue)
(bl )
with internal targeting signals are recognized by specific receptors of the translocase of the
outer mitochondrial membrane (TOM) — that is, by Tom20, Tom22 and/or Tom70. Up to
three dimers of Tom70 are recruited per precursor (each Tom70 structure shown here
represents a dimer). The precursor proteins are then translocated through the Tom40 pore
(the small Tom proteins of the TOM complex — Tom5, Tom6 and Tom7 — are not
shown). The TOM complex contains two or three pores. The -barrel proteins then require
the small Tim proteins (Tim9–Tim10) to guide them through the intermembrane space, and
the
h sorting
i andd assemblybl machinery
hi (SAM complex) l ) ffor iinsertion
i andd assembly
bl into
i the
h
outer membrane. Outer-membrane proteins with single transmembrane spans can be directly
inserted into the outer membrane by the TOM complex. Presequence-containing preproteins
use the presequence translocase of the inner mitochondrial membrane (the TIM23 complex)
for transport across the inner membrane. Tim23 forms a pore in the inner membrane.
Presequence-containing inner membrane proteins can either be directly inserted into the
inner membrane by the presequence translocase or be translocated to the matrix side and
exported into the inner membrane107. It has been reported that the extreme amino terminus
off Tim23
Ti 23 spans theh outer membrane36
b 36 (not
( shown).
h ) Th
The membraneb potential
i l ( ) andd the
h
function of the presequence-translocase-associated import-motor (PAM) complex are
essential for the translocation of presequence-containing proteins into the matrix.
Mitochondrial heat-shock protein-70 (mtHsp70) is the central motor component. It
cooperates with Tim44, Pam16 and Pam18 at the inner membrane and requires the matrix
protein Mge1 (mitochondrial GrpE-related protein-1) for nucleotide exchange. In the matrix,
the mitochondrial processing peptidase (MPP) cleaves off the presequence. Multispanning
inner-membrane proteins with internal signals require the Tim9–Tim10 complex for
transport across the outer membrane and the intermembrane space. The insertion of these
proteins into the inner membrane is catalysed by the twin-pore carrier translocase of the
inner mitochondrial membrane (the TIM22 complex), which uses the membrane potential as
an external driving force. This translocase contains two pores.


The posttranslational processing of integral membrane proteins. 1) During their
ribosomal synthesis,their glycosylation is initiated in the lumen of the endoplasmic
reticulum. 2) After ribosomal synthesis is completed,coated vesicles containing the
protein bud off from the endoplasmic reticulum and move to the Golgi apparatus
where protein processing is completed. 3) Later, coated vesicles containing the
mature protein bud off form the Golgi apparatus and fuse to the membrane for
which the protein is targeted, here shown as the plasma membrane.