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Class 3

The signal hypothesis proposes that cytoplasmically synthesized proteins targeted to the ER use an N-terminal signal sequence to direct them to the ER membrane. The signal sequence emerges from the ribosome and binds to the signal recognition particle (SRP), which delivers the ribosome-nascent polypeptide complex to the SRP receptor in the ER membrane. The signal sequence is then cleaved off by a signal peptidase as the mature protein is translocated across the ER membrane and released into the ER lumen.

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78 views6 pages

Class 3

The signal hypothesis proposes that cytoplasmically synthesized proteins targeted to the ER use an N-terminal signal sequence to direct them to the ER membrane. The signal sequence emerges from the ribosome and binds to the signal recognition particle (SRP), which delivers the ribosome-nascent polypeptide complex to the SRP receptor in the ER membrane. The signal sequence is then cleaved off by a signal peptidase as the mature protein is translocated across the ER membrane and released into the ER lumen.

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Elena Jones
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Proteins and their co-translational translocation

across the ER membrane

CLASS 4
Signal hypothesis
• The signal hypothesis was originally proposed by Günter Blobel and David
Sabatini in 1971, and demonstrated by Blobel and colleagues in 1975.
The signal hypothesis showed that cytoplasmically synthesised proteins
targeted to the ER use a signal sequence to direct them to the ER
membrane

Signal hypothesis
• The major mechanism whereby proteins that insert into or cross a
membrane are synthesized by a membrane-bound ribosome. The first
thirteen to thirty-six amino acids synthesized, termed a signal peptide, are
recognized by a signal recognition particle that draws the ribosome to the
membrane surface by interaction with a docking protein. The signal peptide
may later be removed from the protein.
Proteins and their co-translational translocation
across the ER membrane

 ER signal sequence emerges

 The binding by a signal-recongition particles


(SRP)

 SRP delivers the ribosome/nascent polypeptide


complex to the SRP receptor in the ER
membrane, and GTP binding
The signal hypothesis

A simplified view of protein translocation


across the ER membrane, as originally
proposed.

• When the ER signal sequence emerges


from the ribosome, it directs the
ribosome to a translocator on the ER
membrane that forms a pore in the
membrane through which the
polypeptide is translocated.

• The signal sequence is clipped off


during translation by a signal peptidase,
and the mature protein is released into
the lumen of the ER immediately after
being synthesized.
How ER signal sequences and SRP direct ribosomes to the ER membrane

The SRP and its receptor are thought to act in concert. The SRP binds to both the exposed ER signal sequence and the ribosome,
thereby inducing a pause in translation. The SRP receptor in the ER membrane, which is composed of two different polypeptide
chains, binds the SRP-ribosome complex and directs it to the translocator. In a poorly understood reaction, the SRP and SRP
receptor are then released, leaving the ribosome bound to the translocator in the ER membrane. The translocator then inserts the
polypeptide chain into the membrane and transfers it across the lipid bilayer. Because one of the SRP proteins and both chains
of the SRP receptor contain GTP-binding domains, it is thought that conformational changes that occur during cycles of GTP
binding and hydrolysis ensure that SRP release occurs only after the ribosome has become properly engaged with the
translocator in the ER membrane. The translocator is closed (indicated schematically by the ER-lumenal plug) until the
ribosome has bound, so that the permeability barrier of the ER membrane is maintained at all times.

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