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Recap (Last time at the Hox minor groove width)

Recap (Last time at the Hox minor groove width). Core motif. Clustering of shape is compatible with the Hox expression along the anterior-posterior axis and the ordering on the chromosome. Cofactor binding evokes latent differences in DNA binding specificity between Hox proteins.

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Recap (Last time at the Hox minor groove width)

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  1. Recap (Last time at the Hox minor groove width) Core motif Clustering of shape is compatible with the Hox expression along the anterior-posterior axis and the ordering on the chromosome Cofactor binding evokes latent differences in DNA binding specificity between Hox proteins. Slattery et al . Cell. 2011 Dec 9;147(6):1270-82.

  2. DNA shape indicates how Homeodomain genes have differentiated in evolution (co-evolution) 20.06.2012

  3. Outline • Closely related proteins tend to have similar binding sites preferences which suggest coevolution • Focus on examples of how the minor groove width play a role in coevolution.

  4. Protein Binding Microarray (PBM). The binding sites of 168 HDs To look at coevolution: • Sequence similarity of the HD proteins. Compare to: • Binding sites similarity: a. Minor groove width of the binding sites b. DNA sequence of the binding sites • Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Berger MF, at el. Cell. 2008 Jun 27;133(7):1266-76.

  5. 1.HD proteins 1. Align the sequences based on the pfam secondary structure 2. For similarity matrix: Calculating pair-wise similarity matrix using PAM2.

  6. 2.a.Binding site minor groove width • For each HD we choose the top binding sequences and calculated the average minor groove width. • For similarity matrix: Euclidian distance

  7. 2.b. Binding site sequence • For each HD we have a PWM • For similarity matrix: Using 14 nt window and assign the best pair wise Pearson correlation.

  8. Co-evolution between the proteins and their binding sites • Pearson between the 2 matrixes. 0.4 0.52 0.6

  9. HD that have similar AAs tend to have similar sequence binding sites (which was already shown by Yang et al)

  10. There is a better correlation between protein sequence and the BS sequence

  11. There is a better correlation inside the families between protein sequence and the BS minor groove

  12. The Hox example (BPM mouse)

  13. The Hox example (BPM mouse)

  14. Protein: 0.8147 0.6552 PWM: Minor groove:

  15. The Hox example (BPM mouse)

  16. The Hox example (Selex with cofactor)

  17. The Hox example (Selex monomers)

  18. The Hox example (Drosophila B1H)

  19. The Hox example, from the protein side The AAs in the major groove can’t explain the difference in BS

  20. The Hox example, from the protein side There is correlation between the AAs in the N-terminal tail and the minor groove width preferences for the different Hox

  21. The NKX example

  22. The NKX example Protein 0.7415 PWM Minor groove

  23. The NKX example

  24. Conclusions • There is a coevolution between HDs sequences and their binging sites. • What I would like to say: • Major groove help is achieving specificities between the different HD families, but the minor groove help in achieving specificities inside the families. • What I think we can say: • The sequence of the binding site can help in studying specificities between the different HD families, but shape can help in studying specificities inside the families.

  25. To do • Check if it can help in prediction • Maybe compare to the B1H in Drosophila • Check which are the most important AAs (maybe MI?)

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