Fronda - CMB - PPT - Protein Trafficking

Advanced Cell and Molecular Biology
PROTEIN
TRAFFICKING
Presented by:
JERICHO D. FRONDA
Protein Trafficking
Once protein are made, they must be sent to the correct
location.
There are two mechanisms of protein trafficking:
1. vesicle mediated trafficking - involves protein made in
the endoplasmic reticulum membrane ribosomes
2. non-vesicle mediated trafficking - involves protein made
in free or cytosolic ribosomes
Signal Sequences
Signal sequences direct the protein from the cytoplasm to a particular organelle. For
eukaryotes, there are specific signal peptides that can direct the protein to the nucleus, to
the mitochondria, to the endoplasmic reticulum and other organelles. The signal sequences
are specifically recognized by receptors that are soluble or membrane-bound. Receptors are
soluble for import into the nucleus, but for delivery to the mitochondria, ER or other
organelles receptors are located within the membranes of cellular compartments. These
receptors help guide the insertion of the protein into or through the membrane. Almost all
protein synthesis in eukaryotes is carried out in the cytoplasm using mRNA generated from
the genomic DNA. An exception are a few proteins in the chloroplasts and mitochondria
that are self-generated using their own DNA and ribosomes). Proteins found in any other
compartment or embedded in any membrane must have been delivered to that
compartment by its signal sequence.
Nuclear Localization
Transport through the nuclear pore.
A) The NLS is recognized by the
importin nuclear transport receptor.
B) The complex is moved into the

nucleus.
C) Ran-GTP facilitates the dissociation

of the complex.
D) Ran-GTP and other associated

proteins are exported and Ran-GTP is
hydrolyzed to Ran-GDP in the
cytoplasm to release importin.
Nuclear Localization
Watch video here: https://youtu.be/rjaudsjiGV8
Mitochondrial
Localization
Transport of proteins into the
mitochondria.
Proteins imported into the
mitochondria are recognized by
their signal sequence and
imported in their
linearized/unfolded form through
the translocation channels. The
chaperone protein HSP70 controls
the unfolding and refolding of the
protein once it is imported.
Mitochondrial Localization
Watch video here: https://youtu.be/onY_WGx4FEI
Transport to the Endoplasmic Reticulum
SRP and its receptor SR mediate
movement of proteins through the
ER membrane.
The SRP recognizes the signal
sequence and binds to it and the
ribosome, temporarily arresting
translation. The SRP-polypeptide-
ribosome complex is bound by its
receptor, SR, which positions the
complex on a translocon. Once the
ribosome and polypeptide are
docked on the translocon, the SRP
dissociates, and translation resumes,
with the polypeptide moving through
the translocon as it is being
synthesized.
Transport to the
Endoplasmic
Reticulum
Building on the single-pass
example, if there were another
signal patch after the stop-transfer
sequence, it would act as a start-
transfer sequence, attaching to a
Single-pass transmembrane protein insertion. translocon and allowing the
(1) The signal sequence has allowed the ribosome to dock on a remainder of the protein to be
translocon and newly made polypeptide is threaded through until moved into the ER. This results in a
the stop-transfer sequence. protein with both N- and C- termini
(2) The hydrophobic stop transfer sequence gets “stuck” in the in the ER lumen, passing through
membrane, forcing the rest of the polypeptide to stay in the the ER membrane twice, and with a
cytoplasm as it is translated. cytoplasmic loop sticking out.
Transport to the
Endoplasmic
Reticulum
Insertion of double-pass transmembrane protein.

After the initial stop transfer sequence is embedded in the membrane, a start transfer sequence instructs
the remainder of the peptide to be fed through the translocon, resulting in a protein with both N-terminus
and C-terminus facing the lumen.
It is important to note that there are other configurations of single-pass and multiple-pass membrane
proteins possible. The examples shown are not indicative of all the potential membrane protein
configurations.
Transport to the Endoplasmic Reticulum
Watch video here: https://youtu.be/Lb_eLOKtA2I
Protein trafficking defects in inherited kidney diseases
Mutations affecting sorting of individual proteins or inactivating the epithelial trafficking
machinery have severe functional consequences causing disease. The presence of
mutations leading to protein trafficking defect is indeed a mechanism of pathogenesis
seen in an increasing number of disorders, including about one-third of monogenic
diseases affecting the kidney. In this review, they focus on representative diseases to
discuss different molecular mechanisms that primarily lead to defective protein transport,
such as endoplasmic reticulum retention, mistargeting, defective endocytosis or
degradation, eventually resulting in epithelial cell and kidney dysfunction. For each
disease, they discuss the type of reported mutations, their molecular and cellular
consequences and possible strategies for therapeutic intervention. Particular emphasis is
given to new and prospective therapies aimed at rescuing the trafficking defect at the
basis of these conformational diseases.
Thank You!

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Advanced Cell and Molecular Biology

B) The complex is moved into the

C) Ran-GTP facilitates the dissociation

D) Ran-GTP and other associated

Insertion of double-pass transmembrane protein.

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