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Download MBBS Trafficking of Protein IV Lecture PPT

Download MBBS (Bachelor of Medicine and Bachelor of Surgery) Latest Trafficking of Protein IV Lecture PPT

This post was last modified on 30 November 2021

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misfolded undergoes retrograde

transport

through

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the

ER

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membrane into the cytosol, where

it

is

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subjected

to

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polyubiquitination.

? Following polyubiquitination, it

enters a proteasome, inside which

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it is degraded to small peptides

that exit.

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? Several proteins, including Sec61,

Derlin 1 and the ERAD E3 ligases,

Hrd1 and Doa10, are potential

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ERAD channel candidates.


the nobel Prize in Chemistry 2004

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The Nobel Prize in Chemistry 2004 was

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awarded jointly to Aaron Ciechanover, Avram
Hershko and Irwin Rose "forthediscoveryof
ubiquitin-mediatedproteindegradation."
Ubiquitin-Dependent Degradation

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? Ubiquitin is a small (8.5 kDa, 76 residue) polypeptide that targets

many intracellular proteins for degradation.

? Ubiquitin molecules are attached by non--peptide bonds formed

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between the carboxyl terminal of ubiquitin and the -amino groups

of lysyl residues in the target protein.

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? The residue present at its amino terminus affects whether a protein

is ubiquitinated.

? Amino terminal Met or Ser residues retard, whereas Asp or Arg

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accelerate ubiquitination

? Attachment of a single ubiquitin molecule to transmembrane

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proteins alters their subcellular localization and targets them for

degradation.

? Subsequent degradation of ubiquitin-tagged proteins takes place in

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the proteasome, a macromolecule that also is ubiquitous in

eukaryotic cells.

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Reactions in attachment of ubiquitin to proteins.

E1 - activating enzyme,
E2 - ligase, and

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E3 - transferase
? The terminal COOH of ubiquitin

first forms a thioester.

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? The coupled hydrolysis of PPi by

pyrophosphatase ensures that the

reaction will proceed readily.

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? A thioester exchange reaction now

transfers activated ubiquitin to E2.

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? E3 then catalyzes the transfer of

ubiquitin to the -amino group of a

lysyl residue of the target protein.

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? Additional

rounds

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of

ubiquitination result in subsequent

polyubiquitination

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Proteasome

? The proteasome consists

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of a macromolecular,
cylindrical complex of
proteins, whose stacked
rings form a central pore

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that harbors the active
sites

of

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proteolytic

enzymes

? For degradation, a protein

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thus must first enter the
central pore.
? Entry into the core is

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regulated by the two outer rings

that recognize polyubiquitinated proteins .

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? The regulatory particle recognizes the ubiquitinated

protein which are unfolded by ATPases present in the

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regulatory particles or caps.

? Protease active sites in the core of the proteosome

attack peptide bonds and degrade the protein.

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? Peptides are released into the cytosol for further

degradation by cytosolic peptidases.

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? Both normally and abnormally folded proteins are

substrates for the proteasome.

? Liberated ubiquitin molecules are recycled.

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? The proteasome plays an

important role in presenting

small peptides produced by degradation of various

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viruses and other molecules to MHC class I molecules,

a key step in antigen presentation to T lymphocytes

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? Genetic disorders that result from defects in the genes

that encode ubiquitin, ubiquitin ligases, or

deubiquitinating enzymes include

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Angelman syndrome
Autosomal recessive juvenile Parkinson's disease
Von Hippel-Lindau syndrome, and
Congenital polycythemia

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TRANSPORT VESICLES

? Proteins

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that

are

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synthesized

on

membrane-bound

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polyribosomes and are
destined for the GA or
PM reach these sites
inside transport vesicles

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? Each vesicle has its own

set of coat proteins.
Vesicular Transport

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? Vesicular transport is the predominant mechanism for

exchange of proteins and lipids between membrane-
bound organelles in eukaryotic cells

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? This form of transport involves the movement of various

elements with the aid of the bubble like vesicles created
from the cell membrane

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? It is fundamentally divided into endocytosis and

exocytosis

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? Endocytosis is divided into 3 distinct mechanisms

Phagocytosis

Pinocytosis and

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Receptor mediated endocytosis



Receptor Mediated Endocytosis

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? The major mechanism of vesicular transport between ER

and Golgi.

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? Takes place in the regions of the membranes known as

coated pits

? The coated pits has high concentration of protein

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clarthrin and this mechanism of receptor mediated
endocytosis is the clarthin coated vesicle method

? However there is another method in which the receptor

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mediated endocytosis takes place without the clarthin
coated vesicles

? The SNARE proteins helps in the later type of the

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receptor
Some Types of Vesicles and Their Functions

Vesicle

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Function

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COPI

Involved in intra-GA transport and

retrograde transport from the GA to the

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ER

COPII

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Involved in export from the ER to either

ERGIC or the GA

Clathrin

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Involved in transport in post-GA locations

including the PM, TGN and endosomes

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Secretory vesicles

Involved in regulated secretion from

organs such as the pancreas (eg, secretion

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of insulin)

Vesicles from the TGN

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They carry proteins to the PM and are also

to the PM

involved in constitutive secretion

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