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This lecture was delivered by Dr. Vijay Rao at The Tamil Nadu Dr. M.G.R. Medical University for Proteomics course. It includes: Protein, Motifs, Models, Structure, Threading, Ligands, DNA, Sequence, Transcription, Factors, RNA
Typology: Slides
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Compare all known structures to each other
-^
Compute
distances
between
protein
structures
-^
Classify
and
organize
all
structures
in
a
biologically meaningful way
-^
Discover relationship between structure andfunction.
-^
Use
known
structures
and
folds
to
infer
structure from sequence (Protein Threading)
Discover conserved substructure domain
-^
Discover conserved substructural motifs
-^
Find
common
folding
patterns
and
structural/functional motifs
-^
Study
interactions
between
proteins
and
other
proteins,
ligands
and
(Protein
Docking)
-^
Use known structural motifs to infer functionfrom structure
-^
Many more…
Sequence motifs are becoming increasinglyimportant in the analysis of gene regulation.
-^
How do we define sequence motifs, and whyshould
we
use
sequence
logos
instead
of
consensus sequences to represent them?
-^
Do
they
have
any
relation
with
binding
affinity?
-^
How do we search for new instances of amotif in this sea of DNA?
-^
A central goal in modelling genome regulation isthe
identification
of
transcription
factors
(TFs)
and their target DNA binding sites, expressed asshort nucleotide sequence motif models.
-^
This goal is becoming tractable even for highereukaryotic
genomes
due
to
the
availability
of
annotated
reference
genomes
for
numerous
organisms, large scale protein-DNA interactionand gene expression studies, and advances inregulatory binding site motif inference algorithms.
AGCCAAGCCAAGCCAAGCCAAGCCA AGCCA
Regulatory
regions
Motif –
Binding site???
Gene expression
regulation
Co-regulation
DNA = nucleotide sequence•
Alphabet size = 4 (A,C,G,T)
mRNA (single stranded)
-^
Alphabet size = 4 (A,C,G,U)
mRNA
amino acid sequence
-^
Alphabet size = 20
Amino acid sequence “folds” into 3-dimensional molecule called protein
AATACGAAGTAAAAUACGAAGUAAAsn Thr Lys Stop
GENE
TRANSCRIPTIONACAGTGA
FACTOR
PROTEIN
GENE
TRANSCRIPTIONACAGTGA
FACTOR
PROTEIN
17
Core Promoter – Sufficient for initiation oftranscription; orientation dependent
TFBS – single transcription factor binding site
-^
Regulatory Regions
Transcriptional Unit
-^
DNA sequence transcribed as a single polycistronic mRNA
EXON
TFBS
TATA
TSR
TFBS
TFBS
Core Promoter/Initiation Region (Inr)TFBS
TFBS
Distal Regulatory Region
Proximal Regulatory Region
EXON
TFBS
TFBS Distal R.R.
Module 3
18
Distal enhancer
Distal enhancer
Proximal enhancer
Core Promoter
Chromatin
20
-^
DNA methylation occurs in competition with histoneacetylation
-^
Acetylation promotes open chromatin structure that is permissivefor TF binding to DNA
-^
Methylation of DNA inhibits histone acetylation
-^
Certain TFs promote histone acetylation by recruiting acetylases
-^
Methylation occurs on cytosines
-^
Preferentially on cytosine adjacent to guanines (CG dinucleotides,generally referred to as CpG)
-^
Methylated cytosines frequently undergo deamination to formthymidine (CpG -> TpG)
-^
CpG Islands are regions of DNA where CG dinucleotidesoccur at a frequency consistent with C and Gmononucleotide frequencies
-^
Highlight regions in which histones are acetylated – regions ofactive transcription
Important
to
recognize,
that
promoters
selectively active after early development willnot
be
acetylated
(and
hence
will
be
methylated) in the cell divisions preceding theestablishment of germ cells and therefore willnot have CpG islands.
-^
Lists of genes that have higher or lower CpGfrequencies
than
average
can
misleadingly
appear to have TF binding motifs based onthis compositional characteristic.
