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8/9/2019 Ivonne Molecular 1

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La existencia de las protenas comienza como una cadena lineal de aa, enseguida y

durante la sntesis, estos polipptidos deben plegarse para adoptar sus

configuraciones nativas. Cambios modestos en el ambiente de las protenas pueden

afectar su funcin.


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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 foldingintermediate, Ia and IB, are in rapid equilibrium. the + between intermediates IIA

- - ,

that both convert directly to the NSH2, and that either or both are intermediates in

the rearrangement of IIC to NSH2.


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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) ATPHsp70 (black)weakly binds to the client near Hsp40. (iii) The J-domain of Hsp40 triggers ATP

, .

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


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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 cyclerepeats. This type of molecular chaperone is also known as a chaperonin; it is

- , - ,

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 leftis shown the outside of the

barrel-like structure and on the righta cross section through its center. (B, adapted

from B. Bukace and A.L. Horwich, Cell 92:351366, 1998.)


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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.


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

el sustrato


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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.


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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.


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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 chainSRP 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 | TheSRPFtsY interaction increases the GTP-binding affinity of both proteins, and

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 SRPFtsY complex and recycles the SRP into the cytosol for another

round of ribosome membrane targeting.


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Precursor proteins (brown) with positively charged amino-terminal presequences, -barrelouter-mem rane prote ns ar green , an mu t spann ng nner-mem rane prote ns uewith internal targeting signals are recognized by specific receptors of the translocase of theouter mitochondrial membrane (TOM) that is, by Tom20, Tom22 and/or Tom70. Up tothree dimers of Tom70 are recruited per precursor (each Tom70 structure shown hererepresents 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 notshown). The TOM complex contains two or three pores. The -barrel proteins then requirethe small Tim proteins (Tim9Tim10) to guide them through the intermembrane space, andthe sort ng and assemb y mach nery comp ex) or nsert on and assemb y nto theouter membrane. Outer-membrane proteins with single transmembrane spans can be directlyinserted into the outer membrane by the TOM complex. Presequence-containing preproteinsuse 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 theinner membrane by the presequence translocase or be translocated to the matrix side andexported into the inner membrane107. It has been reported that the extreme amino terminuso m spans the outer membrane not shown). he membrane potent a ) and thefunction 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. Itcooperates with Tim44, Pam16 and Pam18 at the inner membrane and requires the matrixprotein Mge1 (mitochondrial GrpE-related protein-1) for nucleotide exchange. In the matrix,the mitochondrial processing peptidase (MPP) cleaves off the presequence. Multispanninginner-membrane proteins with internal signals require the Tim9Tim10 complex for

transport across the outer membrane and the intermembrane space. The insertion of theseproteins into the inner membrane is catalysed by the twin-pore carrier translocase of theinner mitochondrial membrane (the TIM22 complex), which uses the membrane potential asan external driving force. This translocase contains two pores.


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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 forwhich the protein is targeted, here shown as the plasma membrane.

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