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#mutation

27 public questions tagged with this topic.

Cytoskeleton

What would be the expected effect of a mutation that prevents dynein’s interaction with dynactin?

Cytoplasmic dynein requires adaptor complexes to achieve efficient cargo transport because motor alone exhibits low processivity and weak cargo binding. Dynactin is twenty three subunit complex containing short Arp1 filament, beta-spectrin adaptor, p150Glued subunit with CAP-Gly microtubule-binding domain and coiled-coil dimerization region that binds dynein intermediate chain. Interaction via extended CC1 fragment of p150Glued locks dynein-dynactin together, increasing run length from submicron to several microns by coordinating two motor domains and suppressing detachment. Preventing this interaction by mutating conserved residues in intermediate chain or depleting p50 dynamitin dissociates complex, leaving dynein catalytically active but unable to maintain association with vesicles such as endosomes, phagosomes and mRNA granules. Cellular outcome is reduced retrograde flux, peripheral accumulation, dispersed Golgi and impaired mitotic spindle alignment. Stronger microtubule binding or reversal to plus-end motion does not occur because directionality encoded in AAA ring and linker orientation, not adaptor identity, confirming dynactin primarily as processivity and cargo recruitment factor.

Ref: Schroer Annu Rev Cell Dev Biol; dynactin p150Glued enhances dynein processivity and cargo binding.

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Protein Sorting and Trafficking

What happens when the transferrin receptor is mutated and cannot bind Fe³⁺ at acidic pH?

Iron uptake in proliferating cells depends on transferrin receptor mediated endocytosis tightly coupled to endosomal acidification. At extracellular pH 7.4 holo transferrin carrying two ferric ions binds transferrin receptor 1 homodimer with nanomolar affinity, clusters via AP2 clathrin adaptor and internalizes into early endosomes. Vacuolar ATPase acidifies lumen to about pH 5.5, protonation of transferrin histidines and nearby receptor residues induces conformational opening of transferrin lobes, reducing Fe3+ affinity by orders of magnitude and releasing ferric iron while apo transferrin remains bound to receptor due to retained high affinity at acidic pH. Liberated Fe3+ reduced to Fe2+ by ferrireductase STEAP3, exported through divalent metal transporter DMT1 into cytosolic labile iron pool for use in heme, Fe S clusters or storage in ferritin. Recycling vesicles return complex to plasma membrane where neutral pH dissociates apo transferrin for reuse. If receptor mutation prevents iron release at low pH, transferrin stays iron locked, endosomal iron export fails, cytosol becomes deficient, IRP IRE system upregulates receptor and represses ferritin, but iron does not accumulate in mitochondria nor cause rapid receptor degradation.

Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 13: Endocytosis and Transferrin Iron Transport.

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Cell Cycle Regulation

What happens if the Rb protein is mutated and cannot be phosphorylated?

Retinoblastoma protein Rb functions as central gatekeeper integrating mitogenic signaling with E2F transcription program controlling G1/S restriction point. In quiescent or early G1 cells, Rb exists in hypophosphorylated state, binding E2F1, E2F2, E2F3 through pocket domains A and B, simultaneously recruiting histone deacetylases, SWI/SNF chromatin remodelers, and Polycomb complexes to repress promoters of cyclin E, cyclin A, thymidine kinase, dihydrofolate reductase, and DNA polymerase subunits. Mitogens induce cyclin D-CDK4/6 synthesis downstream of Ras-MAPK and PI3K pathways, which initiates progressive phosphorylation of Rb at serine 780, 795, 807, 811. Subsequent cyclin E-CDK2 mediated hyperphosphorylation fully displaces Rb, liberating E2F to activate S-phase genes. Mutation eliminating CDK phosphorylation sites locks Rb in constantly bound conformation, maintaining E2F repression despite abundant cyclin-CDK activity. Consequently, cells fail to transcribe nucleotide biosynthesis enzymes and replication factors, arresting before S-phase commitment, illustrating how non-phosphorylatable Rb creates dominant negative barrier to proliferation. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.

Ref: Weinberg, Biology of Cancer, 2nd ed., Chapter 8: Rb Pathway. NCBI Bookshelf: Cell Cycle Control.

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Cell Cycle Regulation

What happens if p53 is mutated?

Functional p53 integrates stress signals, including DNA damage, oncogene activation, and hypoxia, to decide between cell cycle arrest, senescence, or apoptosis. Under normal conditions, wild-type p53 accumulates after ATM phosphorylates serine 15 and CHK2 phosphorylates serine 20, displacing E3 ubiquitin ligase MDM2 that normally targets p53 for proteasomal degradation. Transcriptional program includes CDKN1A encoding p21 inhibitor of CDK2-cyclin E and CDK4-cyclin D, causing Rb to remain hypophosphorylated and E2F-dependent S-phase entry genes repressed, imposing G1 arrest to allow repair. If TP53 gene is mutated, common missense mutations in DNA-binding domain producing dominant-negative tetramers, cells lose ability to transactivate p21 and other checkpoint targets, so G1 arrest fails despite DNA damage. Damaged templates proceed into replication, accumulating mutations and chromosomal aberrations driving tumor progression. Mutant p53 does not accelerate apoptosis or permanently block CDK1; instead it disables G1 surveillance and also compromises apoptosis via BAX and PUMA reduction. Consequently, p53 mutation abolishes G1 checkpoint stringency and genomic stability, explaining high prevalence in cancers.

Ref: Vogelstein et al., Nature 2000, Surfing p53 Network; Levine & Oren, Nature Rev Cancer 2009, p53 Mutations.

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Basic Evolution

Which process does NOT introduce new genetic variation?

Random mating reflects key principle in quiz on section e solved pyqs, where evolutionary mechanisms shape genetic variation and adaptation. In this context, Random mating aligns with experimental and theoretical evidence from population genetics, behavioral ecology and molecular phylogeny. Textbooks like Campbell Biology, Futuyma Evolution and Hartl Principles illustrate supporting data. Understanding why Random mating fits helps integrate natural selection, environment.

Ref: Futuyma, Evolution, Variation, Drift, and Speciation Concepts.

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