possess the amino acid sequence KDEL
(Lys-Asp-Glu-Leu) at their carboxyl terminal
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? KDEL-containing proteins first travel to the GA in vesiclescoated with coat protein II (COPII)
? This process is known as anterograde vesicular transport.
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? In the GA they interact with a specific KDEL receptorprotein, which retains them transiently.
? They then return to the ER in vesicles coated with COPI
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(retrograde vesicular transport), where they dissociate from
the receptor, and are thus retrieved
? Certain other non-KDEL-containing proteins also pass to the
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Golgi and then return, by retrograde vesicular transport, to the
ER to be inserted therein.
THE ER FUNCTIONS AS THE QUALITY
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CONTROL COMPARTMENT OF THE CELL? After entering the ER, newly synthesized proteins
attempt to fold with the assistance of chaperones and
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folding enzymes.? Some Chaperones and Enzymes Involved in Folding
That Are Located in the Rough Endoplasmic
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Reticulum:1. BiP (immunoglobulin heavy chain binding protein)
2. GRP94 (glucose-regulated protein)
3. Calnexin
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4. Calreticulin5. PDI (protein disulfide isomerase)
6. PPI (peptidyl prolyl cis-trans isomerase)
1. Calnexin
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? The chaperone calnexin is a calcium-binding protein? located in the ER membrane.
? This protein binds a wide variety of proteins,
including major histocompatibility complex (MHC)
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antigens and a variety of plasma proteins.? Calnexin binds the monoglucosylated species of
glycoproteins that occur during processing of
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glycoproteins, retaining them in the ER until theglycoprotein has folded properly
2. GRP94 (glucose-regulated protein)
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? It is the most abundant protein in the ER lumen, andis ubiquitously present in nucleated cells.
? GRP94 function as molecular chaperones and can
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bind to malfolded proteins and unassembled
complexes.
? They are induced in response to stress, but once the
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stress is removed the GRPs are posttranscriptionally
modified into biologically inactive forms.
3. Calreticulin:
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? Calreticulin, which is also a calcium binding protein,has properties similar to those of calnexin
? But it is not membrane-bound.
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4. Protein disulfide isomerase (PDI):? Protein disulfide isomerase (PDI) promotes rapid
formation and reshuffling of disulfide bonds until the
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correct set is achieved5. Peptidyl prolyl isomerase (PPI):
? It accelerates folding of proline-containing proteins
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by catalyzing the cis?trans isomerization of X-Probonds, where X is any amino acid residue.
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? Misfolded or incompletely folded proteins interactwith chaperones, which retain them in the ER and
prevent them from being exported to their final
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destinations.
? If such interactions continue for a prolonged period of
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time, the misfolded proteins are usually disposed ofby endoplasmic reticulum associated degradation
(ERAD).
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? This avoids a harmful build-up of misfolded proteins.
? In a number of genetic diseases, such as cystic
fibrosis, retention of misfolded proteins occurs in the
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ER, and in some cases, the retained proteins still
exhibit some functional activity
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Conformational Diseases That Are Caused by Abnormalities in
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Intracellular Transport of Proteins and Enzymes due to MutationsEndoplasmic Reticulum Stress
? Maintenance of homeostasis in the ER is important
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for normal cell function.? The unique environment within the lumen of the ER
is disturbed
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o changes in ER Ca2+,
o alterations of redox status,
o exposure to various toxins or
o some viruses
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can lead to reduced protein folding capacity and
the accumulation of misfolded proteins
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? The accumulation of misfolded proteins in the ER isreferred to as ER stress.
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? The cell responds to ES by unfolded protein responseto restore the ER homeostasis.
? The unfolded protein response is initiated by ER
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stress sensors responds in many ways:
1. Transient inhibition of translation to decrease the
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protein load entering the ER.2. Increased expression of chaperons to enhance
protein folding.
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3. Increased synthesis of protein required for
degradation of protein.
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? If the ES persists, cell undergoes apoptosis.? Degradation of misfolded proteins occur after these
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proteins are transported back across the ER intocytosol. (retrotranslocation or dislocation)
? Proteins are degraded in two ways -
A. By lysosomal proteases ? which do not require ATP
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B. By Proteasome ? the proteasomal degradationrequires ubiquitin and ATP.
The protein to be degraded are marked by
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attachment of ubiquitin .
It is major pathway of protein degradation.
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