Download MBBS (Bachelor of Medicine and Bachelor of Surgery) Latest Trafficking of Protein III Lecture PPT
? A number of proteins
possess the amino acid sequence KDEL
(Lys-Asp-Glu-Leu) at their carboxyl terminal
? KDEL-containing proteins first travel to the GA in vesicles
coated with coat protein II (COPII)
? This process is known as anterograde vesicular transport.
? 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
(retrograde vesicular transport), where they dissociate from
the receptor, and are thus retrieved
? Certain other non-KDEL-containing proteins also pass to the
Golgi and then return, by retrograde vesicular transport, to the
ER to be inserted therein.
THE ER FUNCTIONS AS THE QUALITY
CONTROL COMPARTMENT OF THE CELL
? After entering the ER, newly synthesized proteins
attempt to fold with the assistance of chaperones and
folding enzymes.
? Some Chaperones and Enzymes Involved in Folding
That Are Located in the Rough Endoplasmic
Reticulum:
1. BiP (immunoglobulin heavy chain binding protein)
2. GRP94 (glucose-regulated protein)
3. Calnexin
4. Calreticulin
5. PDI (protein disulfide isomerase)
6. PPI (peptidyl prolyl cis-trans isomerase)
1. Calnexin
? 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)
antigens and a variety of plasma proteins.
? Calnexin binds the monoglucosylated species of
glycoproteins that occur during processing of
glycoproteins, retaining them in the ER until the
glycoprotein has folded properly
2. GRP94 (glucose-regulated protein)
? It is the most abundant protein in the ER lumen, and
is ubiquitously present in nucleated cells.
? GRP94 function as molecular chaperones and can
bind to malfolded proteins and unassembled
complexes.
? They are induced in response to stress, but once the
stress is removed the GRPs are posttranscriptionally
modified into biologically inactive forms.
3. Calreticulin:
? Calreticulin, which is also a calcium binding protein,
has properties similar to those of calnexin
? But it is not membrane-bound.
4. Protein disulfide isomerase (PDI):
? Protein disulfide isomerase (PDI) promotes rapid
formation and reshuffling of disulfide bonds until the
correct set is achieved
5. Peptidyl prolyl isomerase (PPI):
? It accelerates folding of proline-containing proteins
by catalyzing the cis?trans isomerization of X-Pro
bonds, where X is any amino acid residue.
? Misfolded or incompletely folded proteins interact
with chaperones, which retain them in the ER and
prevent them from being exported to their final
destinations.
? If such interactions continue for a prolonged period of
time, the misfolded proteins are usually disposed of
by endoplasmic reticulum associated degradation
(ERAD).
? 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
ER, and in some cases, the retained proteins still
exhibit some functional activity
Conformational Diseases That Are Caused by Abnormalities in
Intracellular Transport of Proteins and Enzymes due to Mutations
Endoplasmic Reticulum Stress
? Maintenance of homeostasis in the ER is important
for normal cell function.
? The unique environment within the lumen of the ER
is disturbed
o changes in ER Ca2+,
o alterations of redox status,
o exposure to various toxins or
o some viruses
can lead to reduced protein folding capacity and
the accumulation of misfolded proteins
? The accumulation of misfolded proteins in the ER is
referred to as ER stress.
? The cell responds to ES by unfolded protein response
to restore the ER homeostasis.
? The unfolded protein response is initiated by ER
stress sensors responds in many ways:
1. Transient inhibition of translation to decrease the
protein load entering the ER.
2. Increased expression of chaperons to enhance
protein folding.
3. Increased synthesis of protein required for
degradation of protein.
? If the ES persists, cell undergoes apoptosis.
? Degradation of misfolded proteins occur after these
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
B. By Proteasome ? the proteasomal degradation
requires ubiquitin and ATP.
The protein to be degraded are marked by
attachment of ubiquitin .
It is major pathway of protein degradation.
This post was last modified on 30 November 2021