CELL & MOLECULAR BIOLOGY

Summary of Today's knowledge

Secretory proteins are synthesized in the endoplasmic reticulum (ER) by the initiation of protein synthesis on free ribosomes, binding of SRP to nascent polypeptide, binding SRP, polypeptide, and ribosome to SRP receptor, then dissociation of SRP from its receptor, and translocation across the membrane of the endoplasmic reticulum, and the cleavage of signal sequence. Translation arrest promotes the subsequent translocation of the nascent polypeptide chain through the Sec61 by targeting the entire complex to the rough ER by binding to the SRP receptor on the membrane. This binding leads to the release of SRP from the ribosome and the signal sequence of the growing polypeptide chain. 

Unfolded protein response (UPR) is activated if there's an excess of unfolded protein that's accumulated in the ER. Activation of UPR pathway leads to the expansion of the ER and production of additional chaperones that meet the need for increased protein folding. If these changes are insufficient to adjust protein folding in the ER to a normal level, the sustained activity of the unfolded protein leads to programmed cell death (apoptosis), thereby eliminating cells that are unable to properly fold proteins from the body. There are 3 main receptors associated with this pathway--IRE1, ATF6, and PERK. IRE1 cleaves pre-mRNA of a transcription factor, XBP1. ATF6 is cleaved to produce active ATF6 transcription factor while PERK is a protein kinase that phosphorylates eukaryotic initiation factor 2 (eIF2). 

The fusion of a transport vesicle with its target involves two events. First, the transport vesicle must recognize the correct target membrane; for instance, a vesicle carrying lysosomal enzymes has to deliver its cargo only to lysosomes. Second, the vesicle and target membranes must fuse, delivering the contents of the vesicle to the target organelle. The initial interaction between vesicles and target membranes is mediated by tethering factors and Rab-proteins. 

Also, lysosomal storage diseases such as Gaucher's disease. This disorder is caused by a failure of lysosomes to degrade substances that they normally break down. The resulting accumulation of nondegraded compounds leads to an increase in the size and number of lysosomes within the cell, resulting in pathological consequences to affected organs.
Zellweger syndrome is a recessive genetic disorder that results from mutations in the Pex proteins that are responsible for peroxisomes assembly. Most peroxisome transmembrane proteins are synthesized in the ER and transported in vesicles that fuse to form peroxisomes. Other transmembrane proteins are synthesized on free ribosomes in the cytosol and targeted to the peroxisome membrane by a membrane-targeting signal.
Two protein modifications that occur in the ER: (i) glycosylation and (ii) addition of GPI anchor
The former plays a role in determining protein structure, function, and stability. It helps to prevent protein aggregation in the ER and provides signals that promote protein folding and subsequent sorting in the secretory pathway. Proteins are glycosylated on asparagine residues [N-linked] or Ser or Thr residues [O-linked]. The N-linked sugars added to proteins in the ER are modified within the Golgi. Those proteins destined for lysosomes are phosphorylated by mannose residues and mannose-6-phosphate serves as a targeting signal that directs their transport to lysosomes from the trans-Golgi network. The latter attaches to glycolipids. GPI consists of to fatty acids chain--inositol and ethanolamine.
Lastly, cotranslational translocation is the binding of growing polypeptide chain to the signal recognition particle through a translocon which is driven by protein synthesis while posttranslational translocation is driven by chaperone protein called binding immunoglobulin protein (BiP).