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Cystic Fibrosis ( CF ) is an autosomal recessionary upset that is caused by mutant of the cystic fibrosis transmembrane conductance regulator ( CFTR ) cistron ( Sheppard & A ; Welsh, 1999 ) . CF can ensue in a scope of symptoms including jobs with the lungs, pancreas and even male sterility. In the undermentioned sum-up I will depict the regular map of the CFTR protein and how the mutated signifier leads to CF. In add-on, I will depict interventions that are being developed for patients with CF.

First, I will depict how the wild type CFTR protein maps. The CFTR cistron contains 12 intermembrane spheres, two non-equivalent atomic binding spheres and one regulative sphere ( Jentsch et al. , 2002 ) . Even though the channel simply facilitates inactive conveyance of chloride, the procedure required to change over the channel to an unfastened conformation requires phosphorylation. This procedure begins with a signaling molecule called camp which binds to cAMP-dependent protein kinase A ( PKA ) ( Cheng et al. , 1991 ) . This kinase so acts by phosphorylating the R-domain at one of four possible serine marks. However, they show in their survey that phosphorylating any one of the four serine marks is sufficient to open the chloride channel. Another survey by Anderson et Al. ( 1991 ) shows that ATP straight binds to the atomic binding spheres ( NBD ) of the CFTR protein. Their consequences suggest that in the wild type protein, gap of the channel is dependent on the phosphorylation of the R sphere in add-on to ATP hydrolysis at one of the two NBDs.

Recently it has been found that the binding of these molecules to their receptors alters the conformation of the protein near the entryway of the pore ( Wang et al. 2010 ) . This opens the pore to let the inactive conveyance of chloride ions. This was determined by detecting the ion conveyance in mutations with altered parts in the cytosolic part of the protein. They found some mutations where the ion channel was ever unfastened, even without phosphorylation of the R-domain. From this they concluded that these mutants must hold altered the conformation of the protein similar to the alteration in conformation that is present when the R-domain is phosphorylated in the wild type protein. In this paper, Wang et Al. ( 2010 ) besides suggest a possible mechanism for the shutting of the channel. They found that when ADP was present without any ATP the channels would alter from an unfastened to shut conformation merely when the NBD2 sphere was non mutated. This suggests that ADP binds to the NBD2 to shut the channel when it is no longer needed to be unfastened.

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Following I will depict how mutants in the CFTR protein consequence in CF. The most prevailing mutant found in CF patients is the? F508 mutant characterized by a omission of phenylalanine at the 508th residue of the CFTR protein ( Li, et al. , 1993 ) . It has been found by Li et Al. ( 1993 ) that in the? F508 mutant the protein that is created shows indistinguishable map to that of the wild type protein. This is of import because it suggests that CF is non caused by a nonfunctioning protein, but instead that it must be due to some sort of cellular procedure that does non let the protein to attach to the plasma membrane. Bartoszewski et Al. ( 2008 ) have found that the? F508 mutant creates a higher degree of emphasis on the endoplasmic Reticulum which activates the unfolded protein response. This response has been determined to stamp down the written text of the CFTR cistron in order to cut down the emphasis on the ER ( Bartoszewski, et al. , 2008 ) . It is besides interesting to observe that even in wild type cells, merely about 25-50 % of CFTR proteins produced of all time mature into cell conveyance proteins whereas the remainder are simply destroyed by a ubiquitin regulated devastation tract ( Ward et al. , 1995 ) . This, nevertheless, compares to less than one per centum of the mutant proteins that of all time mature, proposing that in CF patients, non merely is written text of the CFTR cistron suppressed, but besides a greater part of proteins are destroyed.

Since the tract of the CFTR is good studied, many people have looked into schemes to handle CF patients. One intervention that shows high potency is called miglustat ( Norez et al. , 2006 ) . This works by suppressing binding of the mutant CFTR protein with the chaperone protein calnexin in the ER ( Norez et al. , 2006 ) . This prevents the protein from come ining the ubiquitin regulated devastation pathway described above and hence allows the protein to go to the plasma membrane. Since the? F508 mutation still shows effectual ion conveyance capabilities this intervention seems to be rather successful. In add-on Liou et Al. ( 2003 ) have described the benefits of lung organ transplant in CF patients. Through the usage of statistics they show that patients in a class that are predicted to hold 30 % or less survival rates over five old ages are the lone patients that benefit from lung grafts. Patients in a class of predicted endurance rates of 50 % over five old ages really show reduced length of service when given a lung graft. These informations indicate that lung grafts are a last resort intervention.

Above I have described the mechanism by which the CFTR protein maps and how the most common? F508 mutant prevents a functional protein from integrating itself in the plasma membrane. However, this mutant can be treated with the modern drug miglustat. With increased apprehension of the mechanisms involved in the mutant CFTR cistron could come better designed drugs and potentially even a remedy for this familial disease.

Annotated Mentions:

Anderson, M. , Berger, H. , Rich, D. , Gregory, R. , Smith, A. , & A ; Welsh, M. ( 1991 ) . Nucleoside Triphosphates Are Required to Open the CFTR Chloride Channel. Cell, 775-784.

Primary Beginning: Determine that ATP is required non merely for activation of the regulative sphere of CFTR but besides for the Nuclear Binding Domain in order to open the chloride channel.

Bartoszewski, R. , Rab, A. , Twitty, G. , Stevenson, L. , Fortenberry, J. , Piotrowski, A. , et Al. ( 2008 ) . The Mechanism of Cystic Fibrosis Transmembrane Conductance Regulator Transcriptional Repression during the Unfolded Protein Response. The Journal of Biological Chemistry, 12154-12165

Primary Beginning: deltaF508 mutant consequences in reduced written text of CFTR cistron instead than increased devastation of the protein. This occurs due to ER emphasis ensuing in the unfolded protein response.

Bartoszewski, R. , Rab, A. , Jurkuvenaite, A. , Mazur, M. , Wakefield, J. , Collawn, J. , et Al. ( 2008 ) . Activation of the Unfolded Protein Response by deltaF508 CFTR. American Journal of Respiratory Cell and Molecular Biology, 448-457

Primary Beginning: Determine that deltaF508 mutant creates emphasis on the ER and promotes the unfolded protein response where as the wild type CFTR does non.

Cheng, S. , Rich, D. , Marshall, J. , Gregory, R. , Welsh, M. , & A ; Smith, A. ( 1991 ) . Phosphorylation of the R Domain by CAMP-Dependent Protein Kinase Regulates the CFTR Chloride Channel. Cell, 1027-1036.

Primary Beginning: Describes the activation procedure involved in opening the CFTR Chloride channel through cAMP-dependent protein kinase interaction with the R sphere in the CFTR protein

Jentsch, T. , Stein, V. , Weinreich, F. , & A ; Zdebik, A. ( 2002 ) . Molecular Structure and Physiological Function of Chloride Channels. Physiological Reviews, 503-568.

Review Article: Describes the full construction of the CFTR protein.

Li, C. , Ramjeesingh, M. , Reyes, E. , Jensen, T. , Chang, X. , Rommens, J. , et Al. ( 1993 ) . The Cystic Fibrosis Mutation ( deltaF508 ) does non Influence the Chloride Channel Activity of CFTR. Nature Genetics, 311-316.

Primary Beginning: delta F508 mutant ( The most common CF mutant ) does non impact the map of the CFTR protein.

Liou, T. , Adler, F. , Cahill, B. , FitzSimmons, S. , Huang, D. , Hibbs, J. , et Al. ( 2001 ) . Survival Consequence of Lung Transplantation Among Patients with Cystic Fibrosis. Journal of the American Medical Association, 2683-2689.

Primary Beginning: Describe the intervention of CF with lung organ transplant. This method is seen as a last resort therapy for patients near decease.

Norez, C. , Noel, S. , Wilke, M. , Bijvelds, M. , Jorna, H. , Melin, P. , et Al. ( 2006 ) . Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the a-glucosidase inhibitor miglustat. Federation of European Biochemical Societies Letters, 2081-2086.

Primary Beginning: Miglustat prevents binding of CFTR mutation to the chaperone protein calnexin which inhibits the protein debasement tract.

Sheppard, D. , & A ; Welsh, M. ( 1999 ) . Structure and Function of the CFTR Chloride Channel. Physiological Reviews, S23-S45.

Review Article: Gives an overview of the finds made to find that mutants in CFTR are causative for cystic fibrosis. Furthermore it describes briefly how CFTR usually maps.

Wang, W. , Wu, J. , Bernard, K. , Li, G. , Wang, G. , Bevensee, M. , et Al. ( 2010 ) . ATP-independent CFTR channel gating and allosteric transition by phosphorylation. Proceedings of the National Academy of Science ( Published Online before print )

Primary Beginning: Suggest that ADP can shut the ion channel when ATP is non present. Besides suggest a possible mechanism that involves allosteric binding that opens the channel.

Ward, C. , Omura, S. , & A ; Kopito, R. ( 1995 ) . Degradation of CFTR by the Ubiquitin-Proteasome Pathway. Cell, 121-127.

Primary Beginning: Describe the devastation of both wild type and deltaF508 proteins through a ubiquitin regulated tract. Besides suggest that simply barricading the proteasomes involved in debasement will be uneffective because one time marked by ubiquitin the molecules will ne’er maturate to the concluding protein.

Personal Contemplation:

I found it really hard to suit everything I wanted to state in less than 900 words. I learned a batch about the quality control system present in the ER and how it can be damaging. It was besides interesting to larn about how miglustat plants and why it is effectual. I tried to get down this assignment early by first reading reappraisal articles. This gave me a good general apprehension of the procedures involved and was clarified farther with primary beginnings. Finding good articles was likely the most hard portion of the assignment. Overall, the assignment was rather interesting.

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