Dr. Akabas and his colleagues wrote an article about the amino acid residues lining the chloride channel of the cystic fibrosis transmembrane conductance regulator, or CFTR. In 1994, the time when this essay was published, the structures and functions of the cytoplasmic domains have been extensively studied but very little was known about the 12 membrane spanning segments and their relationship to the chloride channel. Mutations in certain residues were also known to be associated with mild clinical diseases, but the structural basis of those changes was unknown. Dr. Akabas came up with his own method in order to figure out the residues lining the channels and yielded a lot of new information with it.
The group of scientists hoped to determine the structure of the channel-forming domains in CFTR. The key experiment, called substituted-cysteine-accessibility method or S.C.A.M, consisted of mutating and substituting 9 consecutive residues in the M1 membrane spanning segment with cysteine in Xenopus oocytes, or eggs. If the mutated channels with cysteine still function, then they assumed that the structures of the mutated and normal channels were similar. Next, they determined the accessibility of the cysteine residue by adding the reagents MTSEA and MTSES, which are highly specific reagents that form a mixed disulfide with a free sulfhydryl covalently linking the reagent to the cysteine. In other words, if the MTSEA and MTSES bond with the cysteine residue and alter the conduction, they can assume the accessibility of the residue and then infer that the side chain of the corresponding wild type residue, or the residue before substitution, lines the channel. This process had been used to determining the structures of ion ch...
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... allow the MTS reagents to reach those residues. This experiment backed up the strong evidence that Arg-347 lined the channel. Dr. Akabas also hypothesized that studies of CFTR would lead to discoveries and insight on the structures of their membrane spanning domains.
Dr. Akabas ended his paper with a summary of his results. He concluded that Gly-91, Lys-95, and Gln-98 all line the CFTR channel and are arranged in a helical formation. Dr. Akabas also talked about the problems and surprises he faced during his experiment, such as a missense mutation of Gly-91 to Arg. In the end, substituted-cysteine-accessibility method exceeded the expectations of many and contributed greatly to our knowledge of the CFTR channel. Even though more research and discovery is being done today, we will always remember Dr. Akabas’s experiment as being the basis of the CFTR science.
Membranes are involved in Cystic Fibrosis when it comes to the genes that are prone to the disease. In a regular functioning body, the CFTR gene helps make the channel that transports charged chloride ions into and out of cell membranes. In a body with cystic fibrosis, the chloride channels don’t function properly, and do not allow chloride ions into and out of the cell membranes, causing the thick mucus (as mentioned earlier) to be produced. The concentration gradients are involved when it comes to moving these molecules and ions across the cell membranes with passive and active transport. Passive transport substances move down concentration gradients while active transport substances move against their concentration gradients (keep in mind this is in a healthy functioning body). With cystic fibrosis, there is a defect in the transport protein, which does not move through the concentration gradient
Cystic Fibrosis (CF) Pathophysiology: Cystic fibrosis is a genetic disease of the secretory glands that affects the respiratory and digestive system. It mainly affects the lungs, pancreas, liver, intestines, sinuses, and reproductive organs. Cystic fibrosis affects the cells that produce sweat, mucus, and digestive fluids. Mucus becomes thick and sticky, causing build-up in the lungs and blocking airways, making it easier for bacteria to develop. This prompts repeated lung infections and can cause severe lung damage after some time.
called an active site. This active site is made by a few of the amino
Receptor tyrosine kinase is a cell membrane receptor system that can trigger multiple cellular responses simultaneously. It requires two receptor tyrosine kinase proteins, which are initially individual polypeptides that each have a signal-binding site, an α helix spanning the cell membrane, and a tail of multiple tyrosines. When signal molecules bind to both proteins they attach through a process called dimerization, forming a dimer. This process activates, or phosphorylates, the ends of the tyrosines, also known as tyrosine-kinase regions. Once the dimer is activated, multiple inactive relay proteins are able to bind to the tyrosine-kinase regions. Each of these proteins trigger a cellul...
In the cells of the late distal tubule and the cortical collecting tubule, the basolateral membrane contains the sodium/potassium ATPase pump and a potassium channel. The apical membrane contains both sodium and potassium channels.[5]
...s to interfere with bonding to the receptors. The final possibility uses CNP, which downregulates the activation in MAP kinase pathways in the chondrocytes (4).
- Bond, I.A. et al., 2002, MNRAS 333, 1 , 71-83 - Figueira, P. et al., 2013, A&A, 557, A93
Specific Aim 3. Define the neutralization escape pathways for each neutralizing Mab. Are there common or unique pathways for each Mab. Is it a stochastic process or does it follow a defined, reproducible pathway due to genetic constraints.
problems within the specific ion channels known to cause the disease. The goal of the
“The plasma membrane is the edge of life, the boundary that separates the living cell from its nonliving surroundings. The plasma membrane is a remarkable film, so thin that you would have to stack 8,000 of these membranes to equal the thickness of the page you are reading. Yet the plasma membrane can regulate the traffic of chemicals into and out of the cell. The key to how a membrane works is its structure” (Simon, 02/2012, p. 60).
of a zwitterion is made possible due to the basic properties of the NH2 group
Immunodeficiency diseases are any diseases that cause an absence or inadequate immune response. They usually effect the immune cells, T-cells, B-cells, complement cells, or phagocytes. Immunodeficiency disease can cause many complications in the body. The compromise of the immune system can eventually lead to death if it is not treated promptly and correctly. A rare immunodeficiency disease that can lead to death is Wiskott-Aldrich Syndrome.
The Wnts are secreted glycoproteins that makes a large family of nineteen proteins in humans hinting to a daunting complexity of signaling regulation, function and biological functions. To date major signaling branches downstream of the Fz receptor have been identified including a canonical or Wnt/β-catenin dependent pathway and the non-canonical or β-catenin-independent pathway which can be further divided into the Planar Cell Polarity and the Wnt/Ca2+ pathways, and these branches are being actively dissected at the molecular and biochemical levels. (Komiya & Habas,
Pauly, S. (2011, February). News from ABC: changes and challenges. Analytical & Bioanalytical Chemistry. pp. 1003-1004. doi:10.1007/s00216-010-4459-0.
7- When describing the properties of JNJ 40279486, the authors highlight the selectivity of the compound over the hERG channel. Explain wh...