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Deuteronomy 6:5-9

Deuteronomy 6:5-9 5 And thou shalt love the LORD thy God with all thine heart, and with all thy soul, and with all thy might. 6 And these words, which I command thee this day, shall be in thine heart:

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Deuteronomy 6:5-9

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  1. Deuteronomy 6:5-9 5 And thou shalt love the LORD thy God with all thine heart, and with all thy soul, and with all thy might. 6 And these words, which I command thee this day, shall be in thine heart: 7 And thou shalt teach them diligently unto thy children, and shalt talk of them when thou sittest in thine house, and when thou walkest by the way, and when thou liest down, and when thou risest up. 8 And thou shalt bind them for a sign upon thine hand, and they shall be as frontlets between thine eyes. 9 And thou shalt write them upon the posts of thy house, and on thy gates.

  2. Protein Localization:The Right Part in the Right Place Timothy G. Standish, Ph. D.

  3. DNA Does Not Specify Proteins DNA sequence does not specify protein, but only the amino acid sequence. The protein is one of a number of minimum free-energy foldings of the same amino acid chain, and the cellular milieu together with the translation process influences which of these foldings occurs … And organisms are not determined by their DNA but by an interaction of genes and the environment, modified by random cellular events. Lewontin, R. 2001 reviewing Who Wrote the Book of Life? A History of the Genetic Code by Lily E. Kay. Science February 16, 2001.

  4. Transcription And Translation In Prokaryotes 5’ 3’ 3’ 5’ RNA Pol. Ribosome mRNA Ribosome 5’

  5. Eukaryotic Gene Expression Cytoplasm Nuclear pores Degradation AAAAAA AAAAAA DNA Transcription Modification RNA RNA Processing G G Degradation etc. Ribosome mRNA G AAAAAA Export Translation Nucleus Packaging Transportation

  6. After Translation • To be effective polypeptide chains must: • Fold correctly - This may involve chaperone protiens • Be modified, if necessary - for example, by glycosylation at specific amion acids • Be in the correct location - Which can be, as we shall see, a complex process

  7. Protein Production and Transport Ribosomes Cytoplasm Nucleus Endoplasmic Reticulum Rough Smooth Gogi Complex

  8. Protein Production Mitochondria and Chloroplasts Cytoplasm AAAAAA Nucleus G Export Mitochondrion Chloroplast

  9. Protein Production Mitochondria and Chloroplasts Cytoplasm Nucleus Mitochondrion Chloroplast

  10. Protein Production Mitochondria Outer membrane Inner membrane Matrix Inter membrane space

  11. Protein Production Mitochondria Outer membrane Leader sequence binding receptor ATP P +ADP ATP P +ADP MLSLRQSIRFFKPATRTLCSSRYLL Inner membrane Inter membrane space Matrix

  12. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Peptidease cleaves off the leader MLSLRQSIRFFKPATRTLCSSRYLL Inner membrane Inter membrane space Matrix

  13. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane MLSLRQSIRFFKPATRTLCSSRYLL Inter membrane space Matrix

  14. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane Inter membrane space Matrix

  15. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Hsp60 Hsp60 Inner membrane Inter membrane space Chaperones Matrix

  16. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane Inter membrane space Mature protein Matrix

  17. Yeast Cytochrome C Oxidase Subunit IV Leader M L S L R Q S First 12 residues are sufficient for transport to the mitochondria I R F F K P A T R T L C S S R Y L P • This leader sequence probably forms an a helix • This would localize specific classes of amino acids in specific parts of the helix • There are about 3.6 amino acids per turn of the helix with a rise of 0.54 nm per turn Neutral Non-polar Polar Basic Acidic MLSLRQSIRFFKPATRTLCSSRYLL

  18. Yeast Cytochrome C1 Leader Charged leader sequence signals for transport to mitochondria First cut Second cut Uncharged second leader sequence signals for transport accross inner membrane into the intermembrane space • Cytochrome c functions in electron transport and is thus associated with the inner membrane on the intermembrane space side • Cytochrome c1 holds an iron containing heme group and is part of the B-C1 (III) complex • C1 accepts electrons from the Reiske protein and passes them to cytochrome c MFSNLSKRWAQRTLSKTLKGSKSAAGTATSYFE-KLVTAGVAAAGITASTLLYANSLTAGA-------------- Neutral Non-polar Polar Basic Acidic

  19. Protein Production Mitochondria Outer membrane Inner membrane Matrix Inter membrane space

  20. Protein Production Mitochondria Outer membrane Leader sequence binding receptor ATP P +ADP ATP P +ADP Peptidease cleaves off the leader Inner membrane Inter membrane space Matrix

  21. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane Inter membrane space Matrix

  22. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane Inter membrane space Matrix

  23. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane Inter membrane space Matrix

  24. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane Inter membrane space Matrix

  25. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane Inter membrane space Matrix

  26. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane Inter membrane space Matrix

  27. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane Inter membrane space Matrix

  28. Protein Production Mitochondria Outer membrane Leader sequence binding receptor Inner membrane Mature protein Note that chaperones are not involved in folding of proteins in the inter membrane space and that they exist in a low pH environment Inter membrane space Matrix

  29. Leader Sequence Receptors Transporting proteins into the matrix actually involves two receptors, one each for the outer and inner membranes: • TOM - A > 500 kD complex ~13.8 nm across composed of ~9 mostly transmembrane proteins in the outer membrane • Tom40 Provides the channel for translocation • Tom5,6,7 Are either assembly factors or part of the channel • Tom20,22 Recognize most mtproteins via cytosol domains • Tom37,70,71Receptor for proteins with internal signal sequences • TIM - Two complexes on the inner membrane: • Tim17-23 Recognizes signal sequence for translocation into the matrix and probably provides the transmembrane channel • Tim44 Binds both Tim17-23 on the matrix side of the inner membrane and Hsp70 chaperone whose high affinity for unfolded proteins helps to draw proteins in. Hsp 70 also binds another chaperone, Mge.

  30. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 Outer membrane Intermembrane T I M 17- 23 Inner membrane TIM44 Matrix Cytosol Hsp70 MGE

  31. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Matrix Hsp70 MGE

  32. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Matrix Hsp70 MGE

  33. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  34. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  35. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  36. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 Peptidease TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  37. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 Peptidease TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  38. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  39. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  40. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Hsp60 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  41. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  42. Alternative Mechanism • There are actually two theories about how the leader operates to localize mtproteins in the inter membrane space: • The first, as shown in the previous slides, involves the whole protein moving into and then out of the matrix • The alternative theory suggests that once the first leader, which targets to the mitochondria is removed, the second leader prevents the protein from ever entering the matrix so it is transported only into the inter membrane space.

  43. Leader Sequence Receptors First part of leader signaling for entrance into mitochondria T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Matrix Hsp70 MGE

  44. Leader Sequence Receptors Second part of leader signals for inter membrane space First part of leader signaling for entrance into mitochondria T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Matrix Hsp70 MGE

  45. Leader Sequence Receptors Second part of leader signals for inter membrane space First part of leader signaling for entrance into mitochondria T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  46. Leader Sequence Receptors Second part of leader signals for inter membrane space T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 First part of leader signaling for entrance into mitochondria TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  47. Leader Sequence Receptors Second part of leader signals for inter membrane space T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 First part of leader signaling for entrance into mitochondria TIM44 Cytosol Outer membrane Intermembrane T I M 17- 23 Inner membrane Hsp70 MGE Matrix

  48. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 TIM44 First part of leader signaling for entrance into mitochondria Cytosol Outer membrane Intermembrane Second part of leader prevents entrance into TIM 17-23 Second part of leader signals for inter membrane space T I M 17- 23 Inner membrane Matrix Hsp70 MGE

  49. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 First part of leader signaling for entrance into mitochondria TIM44 Peptidease Cytosol Outer membrane Intermembrane Second part of leader prevents entrance into TIM 17-23 T I M 17- 23 Inner membrane Matrix Hsp70 MGE Second part of leader signals for inter membrane space

  50. Leader Sequence Receptors T O M 22, 20 T O M 37, 71,70 T O M 40 T O M 5,6,7 Second part of leader prevents entrance into TIM 17-23 Peptidease TIM44 Peptidease Cytosol Outer membrane Intermembrane Polypeptide passes through TOM, but not TIM T I M 17- 23 Inner membrane Matrix Hsp70 MGE Second part of leader signals for inter membrane space

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