Ananya Ghosal, MAKAUT(WB)
Protein Trafficking
The transportation of proteins to the extracellular space or subcellular compartments is called protein trafficking. Protein quality control contains everything from monitoring protein folding, cellular mechanisms, to detecting abnormal forms. Firstly, proteins are synthesized at cytoplasmic ribosomes, and their destinations are determined by transport signals. Cytosolic proteins are those where the growing chain does not contain a transport signal.
Import signals are transported into compartments of mitochondria, the interior of the nucleus, and the peroxisomes. In export signals, the proteins assigned to the secretory pathway pass the endoplasmic reticulum via the Endoplasmic Reticulum/ Golgi Intermediate Compartment (ERGIC), and through the different compartments of the golgi apparatus and finally goes to the plasma membrane. By binding the signal recognition protein, export signals lead to the stoppage of cytoplasmic protein translation. At the ER membrane, the growing chain ribosome and SRP complex (signal recognition particle) are targeted to the translocon complex. Here the translocation restarts through the main component- the translocon, and the translocation in the ER membrane occurs.
Translocation of protein integration occurs simultaneously with protein synthesis. As export signals, secretory proteins contain N-terminal signal peptides. By the use of signal peptidases, signal peptides are cleaved off after the translocation of the growing chain.
Protein Trafficking in Cardiac Arrhythmias
The ion channel current is the sum of biogenic, biophysical, and biochemical properties. Protein trafficking comes under biogenic properties. Cardiac arrhythmias are common and fatal for inherited and acquired diseases which affect the cardiovascular system. Cardiac action results in changes in membrane conductance which controls several electrogenic exchangers and different ion channels.
In the affected ion channels the phenotypes are attributed to “gain of function” or “loss of function”. Reduction of K+ channel current activated throughout the polarization resulting in prolonging of the plateau phase of cardiac action potentials of LQT1,2,5 and 6.
Characterization of LQT1 and 5 are based on a mutation in KCNE1 and KCNQ1 which encode β and α subunits of the K+ ion channels, respectively. Characterization of LQT6 and LQT2 are based on mutation KCNE2 and KCNH2 which encodes putative β and α subunits respectively.
LQT7 occurs due to mutation in KCNJ2 reducing the inward rectifier K+ ion channel current which slows down the return of the membrane to resting potential. LQT4 was associated with abnormalities in ankyrin-B protein, which stimulated the formation of macromolecular signaling complexes which decreases the repolarising current. LQT3 appears from a mutation in hNaV1.5 (SCN5a), which encodes the cardiac Na+ ion channel causing failure of normal inactivation which further increases prolong action potential and late Na+ current.
Defective protein trafficking often appears due to a LQT2 disease mechanism, leading to a reduction in the delivery of channels to the cell surface membrane. Trafficking defective mutations are not restricted to a single region, rather, these are found in several regions of proteins including the transmembrane region, the C-terminus, pore region, and the N-terminus.
Normally trafficking channels and WT (wild-type) channels are differentiated as they are minimally present in the cell membrane. Electrophysiologically, there is minimal or negligible detectable current, mature complex glycosylated protein is absent but immature core-glycosylated protein is present.
Protein Trafficking in Inherited Kidney Diseases
The functional unit of the kidney is the nephron, which contains different types of highly differentiated polarized epithelial cells which ensures vectorial transport of ion and barrier functions, molecules across the apical and basolateral plasma membranes and proteins. Modifying the composition of the primary ultrafiltrate via secretion of necessary solutes and reabsorption produces urine. The function of renal epithelia is to accurately deliver the specific proteins like transporter or channels, on the suitable membrane domain.
Disease-causing severe functional consequences may occur due to the intracellular sorting of individual proteins affected by the mutation or activation of epithelial trafficking machinery. One-third of mutating genes directly interfere with protein transport, which affects one or more segments of the nephron. To reach the final destination protein product enter the secretory pathway. The first step is co-translational translocation in the ER where only properly folded proteins can move forward and that is controlled by the quality control system. When the protein reaches Golgi from ER, they undergo several modifications, the most common one is N-linked glycan.
Complex processes control anterograde and retrograde transport with final destination with trans Golgi network, proteins are sent to apical, endolysosomal, and basolateral compartments. The mechanism of retention in the ER is shared by a vast range of conformational diseases due to the mutations affecting protein folding. The main reason behind the loss of function effect is misfolding mutation as mutated protein is degraded to ER-associated degradation.
Protein reaches its final destination by the process of protein targeting which is controlled by its information contained in the dysregulation and protein sequence that leads to disease. In the absence of the protein function in the physiological cell compartment, the mutation has a loss of function effect.
Due to the deviant localization of functional mutant protein related with a gain of function component. Endocytosis is the basic cellular process that involves the internalization of lipids, plasma membrane proteins, and extracellular molecules. Early and late endosomes and lysosomes are the main components of the mammalian endocytic pathway. The internalization of molecules from the plasma membrane are allowed membrane compartments. Vesicular trafficking can regulate the function of plasma membrane protein as the rate of internalization and insertion alter the amount of plasma membrane.
Protein Trafficking in Alzheimer’s Disease
The characterization of pathological features of Alzheimer’s disease is based on amyloid plaques and neurofibrillary tangles (NFT). Characterization of NFT’s is based on an accumulation of hyperphosphorylated tau which disrupts normal function in particular regions of the CNS that are essential for learning and memory. Amyloid plaques consist of amyloid β peptides, derived from sequential cleavage of the amyloid precursor protein.
In familial form Alzheimer’s disease (FAD), the first causative gene identified is APP (amyloid protein precursor). The cleaving of APP is done by α-, β- and γ- secretases. In the amyloid region, the activity of α- secretase is to cleave APP in the middle, which prevents the formation of amyloid. The α-secretase mediated processing of APP comprises a regulated and constitutive component resulting in the activation by protein kinase C. In amyloidogenic processing, the first proteolytic step is the processing of APP that is catalyzed by BACE1 (Beta-secretase 1) or aspartyl protease.
The nicastrin is retained in the ER due to the absence of PS1. PS1 and nicastrin travel together towards the Golgi and possibly to the plasma membrane. The maturation and trafficking of the γ-secretase substrate enhance due to the deficiency of PS1. Decreasing in the maturation of β-secretases, beta-site APP cleaving- enzyme occurs due to the deficiency of functional PS1. BACE1 and PS1 are bounded in the distal compartment are neurotic processes in the retinoic acid-induced differentiated SH-SY5Y cells. PS1 controls BACE1 activity through facilitating trafficking and direct interaction of BACE1 to the late compartments. BACE1 is located apically or in neurons targeting the axon.
Neurons are highly polarized cells with dendritic and axonal components with elaborate targeting of both β-secretes and APP in a neuron, regulating the amount of Aβ production. PS1 is mostly expressed in the intermediate compartment, in some transport vesicles, the cis-Golgi network, and the ER. However, in the late compartments, PS-mediated γ-secretase cleavage of APP takes place. Γ-secretase is more active in the ER than PS1. Aβ42 β- and γ- secretases could make neurons prone and derangement in the trafficking/transport of APP results in the deposition of senile plaques.
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References:
- Soll, J. (Ed.). (1998). Protein Trafficking in Plant Cells (Vol. 38, No. 1-2). Springer Science & Business Media. https://www.springer.com/gp/book/9780792352372
- Delisle, B. P., Anson, B. D., Rajamani, S., & January, C. T. (2004). Biology of cardiac arrhythmias: ion channel protein trafficking. Circulation research, 94(11), 1418-1428.https://pubmed.ncbi.nlm.nih.gov/15192037/
- Schaeffer, C., Creatore, A., & Rampoldi, L. (2014). Protein trafficking defects in inherited kidney diseases. Nephrology Dialysis Transplantation, 29(suppl_4), iv33-iv44.https://pubmed.ncbi.nlm.nih.gov/25165184/
- Uemura, K., Kuzuya, A., & Shimohama, S. (2004). Protein trafficking and Alzheimer’s disease. Current Alzheimer Research, 1(1), 1-10. https://pubmed.ncbi.nlm.nih.gov/15975080/
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