Download MBBS (Bachelor of Medicine and Bachelor of Surgery) Latest Trafficking of Protein IV Lecture PPT
Scheme of the events in ERAD
? A target protein which is
misfolded undergoes retrograde
transport
through
the
ER
membrane into the cytosol, where
it
is
subjected
to
polyubiquitination.
? Following polyubiquitination, it
enters a proteasome, inside which
it is degraded to small peptides
that exit.
? Several proteins, including Sec61,
Derlin 1 and the ERAD E3 ligases,
Hrd1 and Doa10, are potential
ERAD channel candidates.
the nobel Prize in Chemistry 2004
The Nobel Prize in Chemistry 2004 was
awarded jointly to Aaron Ciechanover, Avram
Hershko and Irwin Rose "forthediscoveryof
ubiquitin-mediatedproteindegradation."
Ubiquitin-Dependent Degradation
? 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
between the carboxyl terminal of ubiquitin and the -amino groups
of lysyl residues in the target protein.
? The residue present at its amino terminus affects whether a protein
is ubiquitinated.
? Amino terminal Met or Ser residues retard, whereas Asp or Arg
accelerate ubiquitination
? Attachment of a single ubiquitin molecule to transmembrane
proteins alters their subcellular localization and targets them for
degradation.
? Subsequent degradation of ubiquitin-tagged proteins takes place in
the proteasome, a macromolecule that also is ubiquitous in
eukaryotic cells.
Reactions in attachment of ubiquitin to proteins.
E1 - activating enzyme,
E2 - ligase, and
E3 - transferase
? The terminal COOH of ubiquitin
first forms a thioester.
? The coupled hydrolysis of PPi by
pyrophosphatase ensures that the
reaction will proceed readily.
? A thioester exchange reaction now
transfers activated ubiquitin to E2.
? E3 then catalyzes the transfer of
ubiquitin to the -amino group of a
lysyl residue of the target protein.
? Additional
rounds
of
ubiquitination result in subsequent
polyubiquitination
Proteasome
? The proteasome consists
of a macromolecular,
cylindrical complex of
proteins, whose stacked
rings form a central pore
that harbors the active
sites
of
proteolytic
enzymes
? For degradation, a protein
thus must first enter the
central pore.
? Entry into the core is
regulated by the two outer rings
that recognize polyubiquitinated proteins .
? The regulatory particle recognizes the ubiquitinated
protein which are unfolded by ATPases present in the
regulatory particles or caps.
? Protease active sites in the core of the proteosome
attack peptide bonds and degrade the protein.
? Peptides are released into the cytosol for further
degradation by cytosolic peptidases.
? Both normally and abnormally folded proteins are
substrates for the proteasome.
? Liberated ubiquitin molecules are recycled.
? The proteasome plays an
important role in presenting
small peptides produced by degradation of various
viruses and other molecules to MHC class I molecules,
a key step in antigen presentation to T lymphocytes
? Genetic disorders that result from defects in the genes
that encode ubiquitin, ubiquitin ligases, or
deubiquitinating enzymes include
Angelman syndrome
Autosomal recessive juvenile Parkinson's disease
Von Hippel-Lindau syndrome, and
Congenital polycythemia
TRANSPORT VESICLES
? Proteins
that
are
synthesized
on
membrane-bound
polyribosomes and are
destined for the GA or
PM reach these sites
inside transport vesicles
? Each vesicle has its own
set of coat proteins.
Vesicular Transport
? Vesicular transport is the predominant mechanism for
exchange of proteins and lipids between membrane-
bound organelles in eukaryotic cells
? This form of transport involves the movement of various
elements with the aid of the bubble like vesicles created
from the cell membrane
? It is fundamentally divided into endocytosis and
exocytosis
? Endocytosis is divided into 3 distinct mechanisms
Phagocytosis
Pinocytosis and
Receptor mediated endocytosis
Receptor Mediated Endocytosis
? The major mechanism of vesicular transport between ER
and Golgi.
? Takes place in the regions of the membranes known as
coated pits
? The coated pits has high concentration of protein
clarthrin and this mechanism of receptor mediated
endocytosis is the clarthin coated vesicle method
? However there is another method in which the receptor
mediated endocytosis takes place without the clarthin
coated vesicles
? The SNARE proteins helps in the later type of the
receptor
Some Types of Vesicles and Their Functions
Vesicle
Function
COPI
Involved in intra-GA transport and
retrograde transport from the GA to the
ER
COPII
Involved in export from the ER to either
ERGIC or the GA
Clathrin
Involved in transport in post-GA locations
including the PM, TGN and endosomes
Secretory vesicles
Involved in regulated secretion from
organs such as the pancreas (eg, secretion
of insulin)
Vesicles from the TGN
They carry proteins to the PM and are also
to the PM
involved in constitutive secretion
This post was last modified on 30 November 2021