Mutation Hotspot Prediction, Structural Analysis & Stability Changes of Prion Protein Involved in Causing CJD

Author Name(s):
Author Email:

Abstract

Creutzfeldt-Jakob disease (CJD) is a rare, degenerative, invariably fatal brain disorder. It affects about one person in every one million people per year worldwide. Creutfeldt-jakob disease is the most frequently seen type of prion diseases. The study on the role of prion protein and its involvement in the occurrence of prion protein is the point to be considered. In the current work the protein structural analysis and mutation prediction has been undertaken for prion protein. Focus was to identify the disorder regions which have maximum probability of mutation which was followed by the effect of mutation on these sites.  The work included a series of steps, collection of the protein sequence from NCBI followed by domain analysis using SMART & GLOB-PLOT. STRING is a database of known and predicted protein-protein interaction which is used to identify the networking proteins for prion protein. The disordered /unstructured regions within a protein sequence were identified by DisEMBL. RONN is used for the prediction of protein disorder with the disorder probability predicted for each amino acid. I Mutant and Polyphen were the two major tools used for the study of effect of mutations on the stability and functions of the protein. For primary structure and secondary structure prediction PROTPARAM and SOPMA were applied. The three-dimensional structure of protein sequence was analysed using Phyre 2.

Introduction

The term “prion”is derived from proteinacious particle and refers to the pathogen that causes transmissible spongiform encephalopathy (TSEs).This small infectious particle is a disease-causing form a protein called cellular prion protein (Prpc) PRNP(PRION PROTEIN) is the human gene encoding for the major prion protein prp (for prion protein or protease-resistance protein).It is also known as CD230(cluster of differentiation 230). Prions are also unique and they don’t contain nucleic acid, unlike bacteria, fungi, viruses and pathogens. The normal prion protein is thought to be made up of flexible coils referred to as alpha helices, but in the abnormally folded form, these helix are stretched out into densely packed structures called beta sheets.

 

Prion discovery:

Mark Rogers in the department of zoology and the Biotechnology center at University College, Dublin:

The term “prion” was coined by Stanley B. Prusiner of the University of California, School of medicine at San Francisco in 1982 to distinguish the infectious agent that causes scrapie in sheep, creutzfeldt-jakob disease (CJD) in humans and bovin spongiform encephalopathy (BSE) in cattle from other, more typical infectious agents. The prion hypothesis postulates that these diseases are caused not by a conventional virus or bacterium but by a protein that has adopted an abnormal form. Prusiner won the Nobel Prize in physiology or medicine 1997 for his research into prion.

Diseases Caused by Prion Protein

There are several diseases of both man and animals whose onset is either directly or indirectly linked to this special protein called prion protein. Some of the diseases caused by it include Scrapie, Bovine Spongiform encephalopathy, Transmissible milk encephalopathy, Chronic wasting disease (CWD), FSE, EUE, CJD etc.

Scrapie was transferred to Scotland in the 1940s. Similar prion diseases are known to affect other animals, e.g., mink, cats, deer and moose. Bovine Spongiform Encephalopathy (BSE) – Mad cow disease is a prion disease that has recently received a great deal of publicity. In England BSE was transmitted to cows through feedstuff supplemented with offals from scrapie-infected sheep. The BSE epidemic first became evident in 1985. Due to the long incubation time the epidemic did not peak until 1992. In this year alone roughly 37,000 animals were affected.

 

Creutzfeldt-Jakob disease (CJD) is a Neurodegenerative Disease that is incurable and invariably fatal  “(CJD (Creutzfeldt–Jakob Disease, Classic)”. Centers for Disease Control and Prevention. 2008-02-26. Retrieved 2009-06-20.) A new variant of CJD that may have arisen through BSE-transmission. Since 1995 about 20 patients have been identified that exhibit CJD-like symptoms. Psychological symptoms with depression have dominated, but involuntary muscle contractions and difficulties to walk are also common. CJD is caused by an infectious agent called prion. Prionsa are misfolded proteins that replicate by converting their properly folded counterparts, in their host, to the same misfolded structure they possess. CJD causes the brain tissue to degenerative rapidly, and as the disease destroys the brain develops and the texture changes to resemble that of a kitchen sponge.

Conclusion:

The above work was aimed to study in detail the sequence properties and the mutational possibility of the prion protein which is a cause of several diseases. The study included the identification of the most

 

 

Mutable site on the protein i.e. the position 53 in the sequence. The effect of mutations to these site were also studied functionally and stability based. Functionally polyphen proved that any mutation to this site causes a probably damaging effect. Thus making it important. Further the 3D structure of the protein was predicted using ITASSER, which produced 5 different structures out of which model 1 being best was selected and shown above.

 

References

HL True, SL Lindquist “A yeast prion provides a mechanism for genetic variation and phenotypic diversity”, Nature 2000

 

S Chen, SP Yadav, WK Surewicz , “S Chen, SP Yadav, WK Surewicz – Journal of Biological Chemistry, 2010 – ASBMB” Journal of Biological Chemistry, 2010 – ASBMB

 

N VassalloJ Herms, “Cellular prion protein function in copper homeostasis and redox signalling at the synapse”, Journal of neurochemistry, 2003 – Wiley Online Library

 

MS Palmer, AJ Dryden, “Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease”, Nature, 1991 – search.proquest.com

 

K Hsiao, Z Meiner, E Kahana, C Cass, “Mutation of the prion protein in Libyan Jews with Creutzfeldt–Jakob disease”, England Journal of Medicine, Volume 324

 

Gasteiger E., Hoogland C., Gattiker A., Duvaud S., Wilkins M.R., Appel R.D., Bairoch A.; Protein Identification and Analysis Tools on the ExPASy Server (In) John M. Walker (ed): The Proteomics Protocols Handbook, Humana Press (2005).
pp. 571-607

 

Yang, ZR, Thomson, R, McNeil, P, and Esnouf, RM (2005). RONN: the bio-basis function neural network technique applied to the detection of natively disordered regions in proteins.

Rune Linding,a Robert B. RussellVictor Neduva, and Toby J. Gibson, GlobPlot: exploring protein sequences for globularity and disorder, Nucleic Acid Research, 2003

Emidio CapriottiPiero Fariselli, and Rita Casadio, I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure”, Nucleic Acid Research, 2005

 

Ivan Adzhubei,1 Daniel M. Jordan,1,2 and Shamil R. Sunyaev1, Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2, Curr Protoc Hum Genet. 2013 Jan; 0 7: Unit7.20.

 

J Yang, R Yan, A Roy, D Xu, J Poisson, Y Zhang. The I-TASSER Suite: Protein structure and function prediction. Nature Methods, 12: 7-8 (2015). (Download the PDF file).

DOWNLOAD THE COMPLETE RESEARCH PAPER PDF

123 total views, 1 views today

About the author: dev