You have a patient that exhibits the beginning symptoms of neurological loss of

Question

You have a patient that exhibits the beginning symptoms of neurological loss of function and decide to sequence the patient’s genome to characterize any genetic markers for disease. You notice a mutation in prion (PrP) protein’s GPI anchor domain.   

A. Describe what mutations would likely cause loss of function (in relation to the GPI anchor and the PTMs of PrP).

B. Describe how you would characterize any problems in the patient’s carbohydrate using biochemistry-based assays.

C. You decide to study the patient’s PrP function in vitro and in vivo. Describe ways you could do that.

D. Propose a function for the octapeptide repeat in PrP.

Explanation / Answer

A) PRION PROTEIN (PrP) or PROTEASE RESISTANT PROTEIN is a human gene encoding for major PrP which is predominant in nervous system. The protein exist in multiple forms i.e., normal PrPc and disease causingPrPsc.

The human protein structure consists of globular domain with three alpha helics, two strand beta sheet, NH2 terminal tail and short COOH terminal tail.

GPI membrane anchor at COOH terminal which attaches PrP to cell membranes.

Thee conversion of normal to disease causing ones is the mechanism of transmission of fatal, neurodegenerative transmissable spongiform encephalopathies (TSE). This can arise from genetic factors.

Some PRNP mutations lead to change in single aminoacids in the prion protein. These mutations cause the cell to make prion proteins with an abnormal structure.

The abnormal protein accumulates in brain and destroys nerve cells which leads to mental and behavioral features of prion diseases.

C) The demonstration of alpha secretase derived from cellular prion protein fragment N1 displays IN VIVO and IN VITRO neuroprotective function by modulating p53 pathway. It further demonstrates distinct N-terminal cleavage products of cellular prion protein harbour different biological activities underlying various phenotypes linking cellular prion protein to cell survival.

D) PrP contains 5 amino terminal octapeptide repaeats with sequence PHGGGWGQ which is thought to generate copper binding domain and deprotonated amide nitrogens. The ability to bind copper is PH dependent. NMR shows copper binding results in a conformational change at N-terminus.

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