protein turnover

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27 Terms

1

what is protein turnover

Replacement of older cells as theyre broken down within the cell

ā€¢Is equal to protein degradation.

ā€¢Many cellular proteins are constantly degraded and resynthesized.

ƘThe total amount of proteins in the body remains constant (Rate of protein synthesis is constant).

ā€¢Many rapidly degraded proteins function as regulatory molecules, such as transcription factors.

<p>Replacement of older cells as theyre broken down within the cell </p><p></p><p><span>ā€¢Is equal to <u>protein degradation</u>.</span></p><p><span>ā€¢Many cellular proteins are constantly degraded and resynthesized.</span></p><p><span>ƘThe total amount of proteins in the body remains constant (Rate of protein synthesis is constant).</span></p><p><span>ā€¢Many rapidly degraded proteins function as regulatory molecules, such as transcription factors.</span></p><p></p>
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2

The rate of protein degradation is related to

the half-life of the protein.

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3

what affects protein turnover

food intake

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4

How can a cell distinguish proteins that are meant for degradation?

ā€¢Damaged or unneeded proteins are marked for destruction by the covalent attachment of chains of a small protein, ubiquitin.

ā€¢

ā€¢Polyubiquitinated proteins are subsequently degraded by a large, ATP-dependent complex called the proteasome.

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ubiquitination def

PTM

  • ubiquitin protein attaches to substrate protein to be degraded

  • 76 AA

<p>PTM </p><ul><li><p>ubiquitin protein attaches to substrate protein to be degraded </p></li><li><p>76 AA</p></li></ul><p></p>
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Ubiquitin structure

has 2 end - N and C terminal

its C-terminal glycine residue binds to the epsilon-amino group of a lysine residue on the target protein, forming an isopeptide bond;

energy for bond formation comes froom hydrolysis of ATP

<p>has 2 end - N and C terminal </p><p><span>its </span><strong><mark>C-terminal</mark></strong><span> glycine residue binds to the epsilon-amino group of a lysine residue on the target protein, forming an isopeptide bond;</span></p><p><span>energy for bond formation comes froom hydrolysis of ATP </span></p>
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Examples of cellular functions regulated by ubiquitination

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ā€¢How cells interpret ubiquitination signal depend on: 2

  • Number of ubiquitin molecules added (mono, multi-mono or poly-ubiquitinated)

  • How ubiquitin molecules linked together (linkage through Lys48 or Lys63)

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Poly-ubiquitinated proteins are targeted for degradation via

the proteosome

ā€¢Protein destruction machine

ā€¢Abundant-ATP dependent protease

ā€¢Found in cytosol and nucleus

<p>the proteosome </p><p></p><p><span>ā€¢Protein destruction machine</span></p><p><span>ā€¢Abundant-ATP dependent protease</span></p><p><span>ā€¢Found in cytosol and nucleus</span></p>
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10

Proteasome recognizes substrate protein via

ā€¢poly-ubiquitin chain.

ā€¢Translocate target proteins into core-degraded.

<p><span>ā€¢poly-ubiquitin chain.</span></p><p><span>ā€¢Translocate target proteins into core-degraded.</span></p><p></p>
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Two general ways of inducing degradation of a specific protein:

1.Activation of a ubiquitin ligase (E3)

-Different protein ligases (E3) for different target proteins.

-

2. Expose degradation signal on the target protein.

- Allows binding to ubiquitin ligase

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1.Activation of a ubiquitin ligase (E3)

-Different protein ligases (E3) for different target proteins.

<p>-Different protein ligases (E3) for different target proteins.</p>
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2. Expose degradation signal on target proteins

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14

Von Hippel-Lindau Syndrome

ā€¢Autosomal dominant disorder (1 in 36,000 individuals).

ā€¢Formation of tumours (noncancerous or cancerous) and cysts in many different parts of the body.

ā€¢Most frequently appeared during young adulthood.

ā€¢

ā€¢It affects: eye, back of the brain, spinal cord, kidneys, adrenal glands or pancreas.

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ā€¢Common tumours:

-Angiomas- enlarged blood vessels in the retina.

-Hemangioblastomas- vascular tumours along the spine.

-Renal and pancreatic tumours.

-Pheochromocytomas- commonly occur in adrenal glands

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what gene is mutated and role

ā€¢Caused by mutations in VHL gene.

ā€¢VHL gene encodes the Von Hippel-Lindau tumour suppressor (pVHL).

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pVHL controls

-Angiogenesis

-Extracellular matrix formation

-Cell metabolism

-Mitogenesis

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role of pVHL

ā€¢Role: part of multi subunit E3 ubiquitin protein ligase (VHL complex).

ā€¢It is the substrate recognition unit of E3 ligase that targets transcription factor HIF-1Ī± (hypoxia induced factor).

ā€¢It binds and ubiquitylates HIF-1Ī± for degradation in conditions of normoxia.

  • IF NORMAL LEVELS OF O2 FACTORS NOT NEEDED

<p><span>ā€¢Role: part of multi subunit E3 ubiquitin protein ligase (VHL complex).</span></p><p><span>ā€¢It is the substrate recognition unit of E3 ligase that targets transcription factor HIF-1Ī± (hypoxia induced factor).</span></p><p><span>ā€¢It binds and ubiquitylates HIF-1Ī± for degradation in conditions of normoxia.</span></p><ul><li><p>IF NORMAL LEVELS OF O2 FACTORS NOT NEEDED </p></li></ul><p></p>
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ā€¢pVHL complex regulates levels of activator TF HIF-1Ī±

ā€¢HIF-1 Ī± regulates cellular response to hypoxia (low oxygen).

ā€¢Switches on genes that promote cell survival and angiogenesis.

E.G. vascular endothelial growth factor (VEGF

<p><span>ā€¢HIF-1 Ī± regulates cellular response to hypoxia (low oxygen).</span></p><p><span>ā€¢Switches on genes that promote cell survival and angiogenesis.</span></p><p><span>E.G. vascular endothelial growth factor (VEGF</span></p>
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20

release of VEGF

ā€¢Stimulate cell proliferation and outgrowth of new capillaries

<p><span>ā€¢Stimulate cell proliferation and outgrowth of new capillaries</span></p>
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ā€¢pVHL complex targets HIF-1Ī± for degradation under normoxic conditions.

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pVHL complex is inactivated in hypoxic conditions, which lead to

increase levels of HIF-1Ī±.

<p><span>increase levels of HIF-1<sup>Ī±.</sup></span></p><p></p>
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Mutations in VHL gene lead to

ā€¢a lack of regulation of cell growth and survival, allowing cells to grow and divide uncontrollably.

ā€¢Normoxia ā€“ but HIF-Ī± is not targeted for degradation.

ā€¢> 370 inherited mutations in VHL gene.

Ƙ80% cases are missense mutations.

20% large germline deletions.

<p>ā€¢a lack of regulation of cell growth and survival, allowing cells to grow and divide uncontrollably.</p><p><span>ā€¢Normoxia ā€“ but HIF-Ī± is not targeted for degradation.</span></p><p>ā€¢&gt; 370 inherited mutations in VHL gene.</p><p>Ƙ80% cases are missense mutations.</p><p>20% large germline deletions.</p>
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ā€¢Some missense mutations are clustered in the Elongin C binding site, which supports its role in VHL protein function.

Missense mutations-

POSTIONS..

ā€¢Arg167Gln - Substitutes Arginine (R) with Glutamine (Q) at position 167

Arg167Trp - Substitutes Arginine (R) with Tryptophan (W) at position 167.

ā€¢is a hotspot mutation in many populations.

ā€¢It was associated with renal cell carcinoma RCC, renal cysts and pheochromocytoma.

<p><span>ā€¢Arg167Gln - Substitutes Arginine (R) with Glutamine (Q) at position 167</span></p><p><span> Arg167Trp - </span><strong>Substitutes Arginine (R) with Tryptophan (W) at position 167</strong><span>.</span></p><p></p><p><span>ā€¢is a hotspot mutation in many populations.</span></p><p><span>ā€¢It was associated with renal cell carcinoma RCC, renal cysts and pheochromocytoma.</span></p><p></p>
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what do the missense mutations cause - functionally

ā€¢Mutation disrupts hydrogen bonding in VHL complex

ā€¢Elongin C binding region destabilised

ā€¢Loss of interaction between pVHL and elonginC

ā€¢No functional VHL complex (E3 ligase)

ā€¢No degradation of HIF1a Ć  increases protein levels

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summary of Von Hippel-Lindau Syndrome

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