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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.
ĆThe 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.
The rate of protein degradation is related to
the half-life of the protein.
what affects protein turnover
food intake
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.
ubiquitination def
PTM
ubiquitin protein attaches to substrate protein to be degraded
76 AA
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
Examples of cellular functions regulated by ubiquitination
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)
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
Proteasome recognizes substrate protein via
ā¢poly-ubiquitin chain.
ā¢Translocate target proteins into core-degraded.
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.
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2. Expose degradation signal on the target protein.
- Allows binding to ubiquitin ligase
1.Activation of a ubiquitin ligase (E3)
-Different protein ligases (E3) for different target proteins.
2. Expose degradation signal on target proteins
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.
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
what gene is mutated and role
ā¢Caused by mutations in VHL gene.
ā¢VHL gene encodes the Von Hippel-Lindau tumour suppressor (pVHL).
pVHL controls
-Angiogenesis
-Extracellular matrix formation
-Cell metabolism
-Mitogenesis
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
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
release of VEGF
ā¢Stimulate cell proliferation and outgrowth of new capillaries
ā¢pVHL complex targets HIF-1Ī± for degradation under normoxic conditions.
pVHL complex is inactivated in hypoxic conditions, which lead to
increase levels of HIF-1Ī±.
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.
Ć80% cases are missense mutations.
20% large germline deletions.
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.
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
summary of Von Hippel-Lindau Syndrome