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296 Cell-Penetrating Peptides: Processes and Applications
14.5 Predictive and Proteome Analyses...............................................................310
14.5.1 Prediction Algorithms ......................................................................310
14.5.1.1 Weight Matrix Methods....................................................311
14.5.1.2 Artificial Neural Network-Based Methods ......................311
14.5.1.3 Global Structure-Based Methods .....................................312
14.5.2 From Proteome to Secretome ..........................................................313
Acknowledgments..................................................................................................313
References..............................................................................................................314
ABSTRACT
Signal peptides are amino-terminal (N-terminal) extensions of polypeptides that
target them from the cytosol to the cytoplasmic (plasma) membrane of prokaryotes
and to the membrane of the endoplasmic reticulum (ER) of eukaryotes. After the
targeting, they direct the linked proteins to translocate the membrane and are usually
cleaved after the translocation. Signal peptides are also called signal sequences or
leader sequences; however, the term “signal sequence” can sometimes be confusing
because of the broader meaning of “protein-sorting signal.” Signals for the translocation
of the mitochondrial inner membrane and the chloroplast thylakoid membrane
are homologs of signal peptides. Although most signal peptides are likely to be
recognized by specific molecules within the cell, some of them spontaneously
interact with the membrane and are inserted into it, at least in vitro. Thus, they are
closely related to so-called cell-penetrating peptides, the main theme of this book.
In addition, understanding signal peptides should be useful for a wide range of
application areas such as biotechnology and clinical investigation.
14.1 BRIEF RETROSPECTION
Günter Blobel was awarded the Nobel Prize in Physiology or Medicine “for the
discovery that proteins have intrinsic signals that govern their transport and localization
in the cell” (from the press release) in 1999, a memorable year for the study
of signal peptides. Of course, there were great pioneers in the study of protein
secretion before Blobel, including George Palade, who shared the Nobel Prize in
Physiology or Medicine with two others in 1974. Palade discovered that secreted
proteins in eukaryotic cells first translocate into the lumen of ER and are then
transported through the Golgi apparatus and secretory vesicles before they are finally
secreted into the outside of the cell. Indeed, Blobel started his major works at Palade’s
laboratory at the Rockefeller Institute. In 1971, Blobel and Sabatini proposed a first
version of the signal hypothesis that the N-terminal extension of secreted proteins
serves as a signal directing them to and across the ER membrane. In 1975, Blobel
and Dobberstein formulated their signal hypothesis based on results of their in vitro
assay system. 1,2
The signal hypothesis states the steps of newly synthesized proteins that translocate
across the ER membrane. In light of current knowledge, the modern version
of the hypothesis can be described as follows: 3-5