PROTEIN FOLDING AND MECHANISM OF PROTEOSTASIS

Presented by MUFASSIRA RAHMAN

1PI14BT013IV semester

Under the guidance ofMr. SUNIL KUMAR

Asst. ProfDepartment of biotechnology

CONTENT

Introduction to protein folding Partially folded proteins Mechanisms to conserve protein folding Chaperone and its classification Chaperone assisted protein folding Clinical focus Conclusion Bibliography

REPLICATION TRANSLATION

Protein Folding

mRna translation Linear sequence of amino acids Primary structure Secondary structure Tertiary structure Quaternary structure

Partially folded proteins

Levinthal's paradox Environmental changes Mutations Amino acid compositions Intrinsically disordered proteins

Folding funnel hypothesisIt represents the change in energy for a large number of folding paths that leads to the native configuration.

Mechanisms to conserve

Endoplasmic reticulum stress

Autophagy mechanism

Spatial compartmentalization

Chaperone protein function

Proteasomes

Chaperone

Set of proteins

Necessary under both normal and stress conditions

Regulation of protein conformation states

Prevent misfolding, accumulation

Stabilize intermediates

Efficient folding of newly-translated proteins

Classification of chaperones

Based on molecular weight Hsp10, Hsp40, Hsp60, Hsp70, Hsp90, Hsp100 Chaperonins Based on interaction Foldases, Holdases, Disaggregases

GroES/GroEL chaperone complex

GroES GroEL ATP Capture (T state) Encapsulation (R’ states) ATP hydrolysis (R’’ state) and substrate release

GroES/GroEL complexTwo rings of GroEL, each composed of seven molecules, form the main chamber of the complex, while one ring of seven GroES molecules forms a cap. Top and bottom views of the complex are shown at left. Individual molecules are shown at right

Proposed pathway for the GroEL/GroES cycle

Protein Disease Cause

Hemoglobin Sickle cell anemia Aggregation

CFTR Protein Cystic fibrosis Trafficking

Huntingtin Huntington's Aggregation

β amyloid Alzheimer's Aggregation

α Synuclein Parkinson's Aggregation

Prion protein(PrP) Creutzfeld Jacob Aggregation

p53 Cancer Trafficking

Conclusion Currently there is no cure for any of these diseases. Concerned research efforts may lead to provide the knowledge for

development of therapeutic strategies. The activity of organized molecules (chaperones) helps to

understand and maintain the homeostasis. Cellular defensive mechanism normally function co-operatively Hence forth, folding & degradation of proteins operate in very

stringent manner to unsure protein aggregation is minimizes.

Reference A mystery unfolds: Franz-Ulrich Hartl and Arthur L. Horwich 2011 J. Clin Invest.; 121(10): 3774–3777. doi: 10.1172/JCI60889

Arthur L. Horwich. 2013. “Chaperonin-mediated Protein Folding”, J. Biol Chem.; 288(33): 23622–23632. doi: 10.1074/jbc.X113.497321

Brandvold KR, Morimoto RI.2015.”The Chemical Biology of Molecular Chaperones--Implications for Modulation of Proteostasis.” J Mol Biol. 427(18): 2931–47vc

Dobson CM.2002; “Protein misfolding diseases: Getting out of shape.” Nature. 418

Enrique Reynaud, Ph.D.; 2010; “Protein Misfolding and Degenerative Diseases” . Nature Education 3(9):28

Jeng W, Lee S, Sung N, Lee J, Tsai FT .2015“Molecular chaperones: guardians of the proteome in normal and disease states.. Doi: 10.12688/f1000research.7214.

Parsell DA, Kowal AS, and Singer MA, et al: 1994” Protein disaggregation mediated by heat-shock protein Hsp104.” Nature. 372(6505); 475(8)

Rampelt H, Kirstein-Miles J, Nillegoda NB, et al.:2012;” Metazoan Hsp70 machines use Hsp110 to power protein disaggregation.” EMBO J.; 31(21): 4221–35.

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”THANK YOU

MUFASSIRA RAHMAN