Protein folding and aggregation

1. Faizan Abul Qais
2013MBM02
Dept. of Ag. Microbiology
PROTEIN FOLDING
AND
AGGREGATION

2. Protein structure
Protein folding
Models of protein folding
Protein Aggregation
Manifestations of protein aggregation
Affecting factors
Diseases associated with protein aggregation
Conclusion
References
Content:

3. Protein Structures
 Primary structure  Secondary structure

4. Protein Structures
 Tertiary structure  Quaternary structure

5. 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.

6. Models of protein folding

7. Protein-energy funnel

8. Energy landscape

9. Protein aggregation
 It is a phenomenon wherein the protein loses its
native structure and adopts a non-native
conformation.
 Despite the many processes that assist in
protein folding, misfolding does occur.
 Failure produces inactive proteins that are
usually toxic in nature.
 Common diseases associated with protein
misfolding are Alzheimer’s, Parkinson’s prion
diseases etc.

10. Overview of protein aggregation

11. Translation Rate and protein folding

12. Protein aggregation results in
 Amyloid fibrils.
 Inclusion bodies.
 Soluble oligomers.

13. 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.

14. 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.

15. Affecting factors
Sequence based
Hydrophobicity
Net charge
Secondary structural
propensities
Environment based
Protein concentration
pH
Temperature
Salt conc.

16. Some associated diseases
Diseases Protein
involved
Modification Manifestation
Alzheimer’s
disease
Amyloid-β Aberrant processing Extracellular amyloid
plaques
Parkinson’s
disease
α-Synuclein Aberrant ubiquination Cytoplasmic
inclusion bodies
Sickle cell anemia Hemoglobin Substitution of Glu to
Val
Sickle shaped RBC
Huntington’s
disease
Huntingtin Poly-glutamine
(CAG) mediated
protein aggregation
Intranuclear inclusion
bodies

17. Conclusion
 Protein aggregation results in the formation of
amyloid fibrils and inclusion bodies which are
associated with many neurodegenerative
disorders and prions related diseases.
 Understanding the structure and mechanistic
aspects might provide a solution to many
possible therapies.
 A key one might be able to find a small
molecule (drug) targeting for the disruption of
misfolded one.

18. Refrences
 Horwitz MS, Scharff MD, Maizel JV Jr. 1969. Synthesis and assembly of adenovirus 2. I.
Polypeptide synthesis, assembly of capsomeres, and morphogenesis of the virion. Virology
39:682–94
 Ingolia NT, Ghaemmaghami S, Newman JR, Weissman JS. 2009. Genome-wide analysis in vivo of
translation with nucleotide resolution using ribosome profiling. Science 324:218–23
 Komar AA. 2009. A pause for thought along the co-translational folding pathway. Trends
Biochem. Sci. 34:16–24
 Zhang G, Hubalewska M, Ignatova Z. 2009. Transient ribosomal attenuation coordinates protein
synthesis and cotranslational folding. Nat. Struct. Mol. Biol. 16:274–80
 Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, et al. 2007. A “silent” polymorphism in
the MDR1 gene changes substrate specificity. Science 315:525–28
 Evans MS, Sander IM, Clark PL. 2008. Cotranslational folding promotes beta-helix formation and
avoids aggregation in vivo. J. Mol. Biol. 383:683–92
 http://en.wikipedia.org
 “A journey from amino acid to protein” by Saad Taiyab
 J, Deutsch C. 2008. Electrostatics in the ribosomal tunnel modulate chain elongation rates. J.
Mol. Biol. 384:73–86
 Hurtley SM, Helenius A. 1989. Protein oligomerization in the endoplasmic reticulum. Annu. Rev.
Cell Biol. 5:277–307