Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 219

domain-containing protein family, such as KE04p and C8orf2. These pro-
teins are essential for the maintenance of lipid-raft-like structures. Although
it is known that the ER has lower levels of cholesterol and glycosphingolip-
ids than the plasma membrane and other organelles, two proteins homolo-
gous to KE04p and C8orf2, Erlin-1 and Erlin-2 (for ER lipid-raft protein),
are found in the ER, suggesting the existence of lipid-raft-like domains in
the ER ( Browman et al., 2006 ).
Another protein involved in the maintenance of lipid-raft-like domains
is the sigma-1 receptor chaperone (Sig-1R), a cholesterol-binding protein
( Hayashi and Su, 2010 ). Sig-1R is also involved in mitochondria-ER bind-
ing through microdomains enriched in cholesterol and ceramides ( Hayashi
and Fujimoto, 2010 ), which form part of the mitochondria-associated ER
membrane (MAM) structure.
2.2. Functions of Endoplasmic Reticulum
2.2.1. Protein Synthesis in Endoplasmic Reticulum
Proteins targeted to the ER and other organelles or destined for secretion
must be incorporated into the ER. Nascent polypeptides possess a signal
sequence in their N-termini that targets them to the ER. This sequence
is not conserved and generally contains hydrophobic amino acids in the
core region. This sequence is recognized by the signal recognition particle
(SRP), consisting of six polypeptides bound to a small RNA, which cycles
between the cytoplasm and the ER membrane. When the SRP recognizes
and binds to the signal sequence of nascent polypeptides, a pause in transla-
tion occurs. Then, the SRP-ribosome complex translocates from the cyto-
plasm to the SER membrane and binds to the SRP Receptor (SR) ( Corsi
and Schekman, 1996 ). Once this process is complete, the SRP and SR
are released, and the nascent polypeptide is translocated by the translo-
con complex (TC) formed by more than 25 polypeptides ( Nikonov and
Kreibich, 2003 ). The core of the TC is Sec61, a protein required for the
translocation of both secretory and membrane proteins. In mammals, Sec61
is a complex formed by three subunits: Sec61α, Sec61β and Sec61γ. This
complex possesses ribosomal binding sites, and its structure forms a pore
through which the polypeptide traverses the membrane. The translocation-
associated membrane protein (TRAM), another integral membrane protein
component of the TC is required for the translocation of some precursors,
like ppαF. The above-mentioned process is known as cotranslational translo-
cation; however, targeting to the ER can also occur posttranslationally. This
event occurs independently of SRP in both yeast and mammalian cells. In