Cell Biology Jigsaw

Question 1

Lamin nuclear pore structure formation

Answer 1

Lamin synthesis

• Lamin A proteins are made in cytoplasm
• Importins bind to nuclear localization signal and go through nuclear pore
• Ran-GTP binds to importin/lamin complex and causes release of lamin

Lamin nuclear pore structure

• Lamins are under nuclear envelope
• Lamins bind to receptors on inner nuclear membrane
• Lamins bind to chromatin
• Lamins bind to transcription factors
• Lamins bind to Wrn helicase

*Mutations in Lamin result in mislocalization on proteins/chromatin on nuclear envelope

Question 2

Muscle Dystrophy

Answer 2

Lamin Dimer formation in Normal People

-Lamins form dimers by using rod-like domains to coil around each other

Lamin Dimer formation in people with Muscle weakness

• Mutation in rod-like domain prevents dimerization
• No dimerization of lamins disturbes structural integrity of nucleus
• Since lamins are intermediate filaments, mutations in inermediate filaments or lamin can cause muscular dystrophy
• Ongoing muscle contraction stresses already less stable

nuclear structure

Question 3

Progeria

Answer 3

Processing in Normal people

• Lamin A protein has extra amino acids that can serve as attachment site for a lipid
• Site where lipid attaches along with other amino acids in that area is cleaved at cleavage site by a protease.

Processing in Progeria patients

• Lipid tail attaches to Lamin
• Cleavage site on Lamin has been made less recognizable by single nucleotide mutation
• Lipid tail remains and can associate with membrane in the wrong manner.

Question 4

Atypical Werner Syndrome

Answer 4

1. Mutation in lamin A that disurpts lamin A’s association with Werner helicase can result in the helicase being misdistributed resulting in Werner syndrome
2. Werner syndrome
   
   1. Inc in DNA mutations
   2. Inc aging

Question 5

Coagulation Deficiency

Answer 5

1. Clotting factors FV and FVIII were found in very reduced levels in circulation.
2. Mutation in both LMAN and MCFD2 prevents secretion of these factors.
   
   1. LMAN binds to COPII subunit involved in production of vesicle that secretes clotting factor.

Question 6

Griscelli Syndrome

Answer 6

• Type 1- Mutation in MyosinVA results in neurological deficit and pigment problem
  
  • Myosin VA binds to actin
• Type 2: Mutation in Rab27a results in immunological problems and pigment problem
  
  • Rab27-GTP binds to membrane of melanosome
  • In immune system, no other Rab can take over function of Rab27a
    
    • Granules in immune system mediate death of target cell by using Rab27a to fuse with target cell.
• Type 3: Mutaiton in melanophilin results in pigment problem only
  
  • Melanophilin connects Rab27a to Myosin VA

Question 7

Hypercholesteralemia

Answer 7

Transport of LDL into cell is receptor mediated

1. LDL binds to LDL receptor
2. LDL is incorporated into coated pit
3. LDL is transported to endosome and later lysosome
4. Receptor is recycled back to cell surface

*Mutation in LDL receptor in the LDL binding domain or LDL C-terminus that interacts with adaptin which then connects receptor to clathrin to form coated pit.

*These mutations prevent cell from uptaking LDL and results in an increase in LDL in the circulation.