School of Biomedical Engineering and Health Sciences,

Faculty of Engineering, UTM.

SMBE 4413: Biochemistry for Biomedical Engineers

Assignment 1: Protein Misfolding and Diseases

Lecturer: Dr Norhana Binti Jusoh

Name: Lim Jia Hui

Matric Number: A16MB0077
1.0 Protein Misfolding

The majority of protein molecules must fold into defined three-dimensional structures to
acquire functional activity. For many proteins, the most prominent structural motif of the
functional protein in its native conformation is known as the alpha helix, a right-handed spiral coil
[1]. When a protein becomes toxic, an extensive conformational change occurs, and it acquires a
motif known as the beta sheet. Note that the beta sheet conformation also exists in many functional
native proteins, such as the immunoglobulins, but the transition from alpha helix to beta sheet is
characteristic of amyloid deposits. The abnormal conformational transition from alpha helix to
beta sheet exposes hydrophobic amino acid residues and promotes protein aggregation [2].

The toxic proteins often interact with other native proteins and may catalyze their transition
into a toxic sate, and hence they are called infective conformations. The newly formed toxic
proteins can repeat this cycle to initiate a self-sustaining loop; thereby amplifying the toxicity to
generate a catastrophic effect, beyond homeostatic reparative mechanisms, to eventually impair
cellular function or induce cellular demise [3].

Fig.1 below shows the misfolding of the protein. A conformational change in a normal protein
seems to be the hallmark event in a group of diverse diseases. Protein misfolding may be associated
to disease by either the absence of biological activity of the folded protein or by a gain of toxic
activity by the misfolded protein. Aggregation of the misfolded protein may also contribute to the
disease pathogenesis [4].
2.0 Protein Folding Disorders

Protein folding disorders are characterized into two groups. The first group involves disorders known
as amyloidosis, characterized by accumulation of wrongly folded proteins as unfolded proteins.
Alzheimer’s Disease is the well-known example of this group. On the other hand, the second group is
characterized by incomplete folding of protein due to minor error in the genetic blueprint, affecting its
physiological function [4].

2.1 Alzheimer’s Disease

Alzheimer’s Disease is a progressive neurological disease of the brain characterized by

presence of protein aggregates and irreversible loss of intellectual abilities, like reasoning and
memory; thereby detrimentally affecting the normal social and occupational lifestyle of the
individual [5].

Proteins function properly when their constituent amino acids fold correctly. On the other
hand, misfolded proteins assemble into insoluble aggregates with other proteins and can be toxic
for the cells. The gradual accumulation of misfolded proteins in the absence of their appropriate
clearance can cause amyloid disease, the most prevalent one being Alzheimer’s Disease.
Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the
accumulation of abnormally folded Amyloid-beta proteins in the brains of AD patients. At the
neuropathological level, Alzheimer’s Disease is characterized by the cellular build-up of misfolded
proteins, like as Amyloid-β and cerebral amyloid aggregates (CAA) in brain, intracellular
aggregates of tau protein in the neurofibril tangles and extracellular aggregates of Amyloid-β in
the senile plaques.

Amyloid-β monomers are soluble and contain short regions of beta sheet and polyproline
II helix secondary structures in solution. Amyloid-β is a short peptide that is a proteolytic
byproduct of the transmembrane protein amyloid precursor protein (APP), whose function is
unclear but thought to be involved in neuronal development. The presenilins are components of a
proteolytic complex involved in APP processing and degradation. Although Amyloid-β is
harmless but at sufficiently high concentration, they undergo a dramatic conformational change to
form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils. Fig. 2 below shows
the amyloid fibrils. The amyloid fibrils will deposit outside neurons in dense formations known
as senile plaques or neuritic plaques, in less dense aggregates as diffuse plaques, and sometimes
in the walls of small blood vessels in the brain in a process called amyloid angiopathy or
congophilic angiopathy.

Alzheimer’s Disease is also considered a tauopathy due to abnormal aggregation of the tau
protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize
microtubules in the cell cytoskeleton. Like most microtubule-associated proteins, tau is normally
regulated by phosphorylation; however, in Alzheimer’s Disease patients, hyperphosphorylated tau
accumulates as paired helical filaments that in turn aggregate into masses inside nerve cell bodies
known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaque
Reference
[1] Pauling, L., Corey, R. B. & Branson, H. R. The structure of proteins: Two hydrogen-bonded helical
configurations of the polypeptide chain. PNAS 37, 205–211 (1951)

[2] Reynaud, E. (2010) Protein Misfolding and Degenerative Diseases. Nature Education 3(9):28

[3] Soto, C. (2001). Protein misfolding and disease; protein refolding and therapy. FEBS Letters.
https://doi.org/10.1016/S0014-5793(01)02486-3

[4] Pietzsch, J. Protein Folding diseases. http://www.nature.com/horizon/proteinfolding/background/

disease.html

[5] Mirza Z, Ali A, Ashraf GM, Kamal MA, Abuzenadah AM, Aga C, Damanhouri GA, Sheikh IA.
Proteomics Approaches to Understand Linkage Between Alzheimer’s Disease and Type 2 Diabetes
Mellitus. CNS & neurological disorders drug targets. 2013