Faizan Abul Qais

2013MBM02

Dept. of Ag. Microbiology

PROTEIN FOLDING

AND

AGGREGATION

Protein structure

Protein folding

Models of protein folding

Protein Aggregation

Manifestations of protein aggregation

Affecting factors

Diseases associated with protein aggregation

Conclusion

References

Content:

Protein Structures Primary structure Secondary structure

Protein Structures Tertiary structure Quaternary structure

Protein Folding

Process by which a protein assumes its functional

conformation.

Factors that guide in proper protein folding are:

(i). Amino acid sequence

(ii). Cellular environment

The folded 3-D structure of most proteins represent a

compromise between thermodynamic stability and

the conformational flexibility required for function.

A substantial fraction of proteins in eukaryotic cells(∼30%) are classified as intrinsically unstructured, such

proteins are prone to aggregation.

Models of protein folding

Protein-energy funnel

Energy landscape

Protein aggregation

It is a phenomenon wherein the protein loses itsnative structure and adopts a non-nativeconformation.

Despite the many processes that assist inprotein folding, misfolding does occur.

Failure produces inactive proteins that areusually toxic in nature.

Common diseases associated with proteinmisfolding are Alzheimer’s, Parkinson’s priondiseases etc.

Overview of protein aggregation

Translation Rate and protein folding

Protein aggregation results in

Amyloid fibrils.

Inclusion bodies.

Soluble oligomers.

Inclusion bodies Dense particles of

aggregated proteins. These are porous and

hydrated. Exhibit amorphous as well

as partly ordered structure. Structural heterogeneity is

observed. Proteins prone to form

inclusion bodies are exposed hydrophobic patches.

Amyloid fibrils

Generic property of all proteins.

Associated with a number of fatal

diseases.

Fibrils take the form of a β-sheet, hence

the name β-amyloid.

Accumulate in variety of organs.

Once formed, they are nearly

indestructible and controlling their

growth is impossible.

Affecting factors

Sequence based

Hydrophobicity

Net charge

Secondary structural propensities

Environment based

Protein concentration

pH

Temperature

Salt conc.

Some associated diseasesDiseases Protein

involved

Modification Manifestation

Alzheimer’s disease

Amyloid-β Aberrant processing Extracellular amyloid

plaques

Parkinson’sdisease

α-Synuclein Aberrant ubiquination Cytoplasmic

inclusion bodies

Sickle cell anemia Hemoglobin Substitution of Glu to

Val

Sickle shaped RBC

Huntington’sdisease

Huntingtin Poly-glutamine

(CAG) mediated

protein aggregation

Intranuclear inclusion

bodies

Conclusion

Protein aggregation results in the formation ofamyloid fibrils and inclusion bodies which areassociated with many neurodegenerativedisorders and prions related diseases.

Understanding the structure and mechanisticaspects might provide a solution to manypossible therapies.

A key one might be able to find a smallmolecule (drug) targeting for the disruption ofmisfolded one.

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