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Bioinformatics for biomedicine Seminar: Sequence analysis of a favourite gene Lecture 5, 2006-10-17 Per Kraulis http://biomedicum.ut.ee/~kraulis What is bioinformatics? Basic databases and tools Sequence searches: BLAST, FASTA Multiple alignments, phylogenetic trees

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Bioinformatics for biomedicine seminar sequence analysis of a favourite gene l.jpg

Bioinformatics for biomedicineSeminar: Sequence analysis of a favourite gene

Lecture 5, 2006-10-17

Per Kraulis

http://biomedicum.ut.ee/~kraulis


Course design l.jpg

What is bioinformatics? Basic databases and tools

Sequence searches: BLAST, FASTA

Multiple alignments, phylogenetic trees

Protein domains and 3D structure

Seminar: Sequence analysis of a favourite gene

Gene expression data, methods of analysis

Gene and protein annotation, Gene Ontology, pathways

Seminar: Further analysis of a favourite gene

Course design


From the previous lecture l.jpg
From the previous lecture

  • 3D structure

    • Relation to function

    • Methods of determination

    • Databases

  • Domains

    • Definition

    • Relation to function

    • Databases


3d structure and sequence 1 l.jpg
3D structure and sequence, 1

  • Sequence determines structure

  • Anfinsen’s experiments: folding

  • 3D structure prediction should work!

    • First principles (physics)

      • Extremely difficult

      • Only special cases

    • By similarity

      • Works reasonably

      • Depends on many factors


3d structure and sequence 2 l.jpg
3D structure and sequence, 2

  • Similar sequence -> similar structure

    • General statement

    • No “real” counterexamples

      • But a designed, extreme case exists

  • A single 3D structure represents a family

    • Depending on sequence similarity

  • Many sequences “allowed” for a structure


3d structure and sequence 3 l.jpg
3D structure and sequence, 3

  • Many sequences “allowed” for a structure

    • Sequence divergence possible over time

  • Structure more conserved that sequence

    • Sequence may diverge beyond recognition

    • Structure may still be similar

    • Apparently unrelated sequences may form similar structures!


3d structure and sequence 5 l.jpg
3D structure and sequence, 5

  • Protein design

    • Target: A given structure

    • Specify a sequence that folds into it

  • Some success in recent years

    • First principles approach

      • Computational prediction

    • Evolutionary approach

      • In vitro evolution experiments


3d structure and sequence 4 l.jpg
3D structure and sequence, 4

  • Example: TIM barrel

    • TIM = Triose isomerase

    • Example in PDB: 1TRI

    • Symmetrical, 8 alpha-beta units

    • Enzymes

      • Wide range of reactions, substrates

  • Some TIM barrels have no significant sequence similarity

    • Sequence divergence?

    • Structure convergence?


Structure database l.jpg
Structure database

  • PDB database

    • At RCSB: http://www.rcsb.org/pdb/

    • Via UniProt: http://www.ebi.uniprot.org/

  • Many different 3D viewers

    • KiNG (uses Java)

    • RasMol (requires installation)


Unknown sequence l.jpg
Unknown sequence?

  • Given unknown sequence, what to do?

    • Set up a check list

      • Never optimal

  • Note: Unrealistic exercise

    • “Premier tool of analytic chemistry: the phone”

    • Consider known facts before analysis

    • Consider the underlying problem


Check list outline l.jpg
Check list, outline

  • Where to search first?

    • UniProt

    • Pfam

    • Ensembl

  • Function?

    • Annotation

    • Similarities

    • Domains, structure


Slide12 l.jpg
Unk1

  • File “unk1-seq.txt”

  • Human protein

  • No other info


Unk1 caspase 8 l.jpg
Unk1 = Caspase 8

  • Protease

    • Cysteine peptidase C14

    • Cascade, activation of others

  • Hormone-triggered

    • TNF (tumor necrosis factor)

  • Multicellular organisms

    • Apoptosis (programmed cell death)

    • Development, cancer


Slide14 l.jpg
Unk2

  • File “unk2-seq.txt”

  • From C. elegans

    • Result of genetic screen

  • Orthologue in human?


Unk2 nhr 25 l.jpg
Unk2 = nhr-25

  • Nuclear receptor (NR) family

    • Transcription factor

    • DNA-binding domain

    • Hormone-receptor domain

  • Orphan NR

    • Unknown ligand; maybe none

  • Multicellular organisms

    • Developmental processes

      • Moulting in insects


Slide16 l.jpg
Unk3

  • File “unk3-seq.txt”

  • Mouse protein

  • No other info


Unk3 gpr141 l.jpg
Unk3 = GPR141

  • GPCR

    • G-protein coupled receptor

    • 7TM, seven transmembrane helices

  • Orphan GPCR

    • Unknown ligand

  • Human ortholog, Ensembl search

    • http://www.ensembl.org/Multi/blastview/BLA_4CBTgZfhK


Task for this week l.jpg
Task for this week

  • Perform analysis of sequences

    • http://biomedicum.ut.ee/~kraulis/bioinfo_biomed/

    • unk4-seq.txt (Danio rerio, zebrafish)

    • unk5-seq.txt (human, fragment)

  • Organism?

  • Protein family?

  • Structure and function?

  • Human medical relevance?


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