Download MBBS Trafficking of Protein III Lecture PPT

? A number of proteins

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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 vesicles

coated 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 receptor

protein, 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. Calreticulin
5. 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 the
glycoprotein has folded properly


2. GRP94 (glucose-regulated protein)

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? It is the most abundant protein in the ER lumen, and

is 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 achieved

5. Peptidyl prolyl isomerase (PPI):
? It accelerates folding of proline-containing proteins

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by catalyzing the cis?trans isomerization of X-Pro

bonds, where X is any amino acid residue.

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? Misfolded or incompletely folded proteins interact

with 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 of

by 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 Mutations
Endoplasmic 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 is

referred to as ER stress.

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? The cell responds to ES by unfolded protein response

to 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 into
cytosol. (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 degradation

requires 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.