group members: wayne christopher, ph.d. bob edgar, ph.d. duncan brown dan holliman

1

UC Berkeley PhylogenomicsKimmen Sjölander http://phylogenomics.berkeley.edu

kimmen@uclink.berkeley.eduAlgorithm & tool development for protein structure-function

prediction.

Investigation of innate immunity in plants and animals: Brian Staskawicz (Plant & Microbial Biology)Barbara Baker (Plant & Microbial Biology)Richard Michelmore (UCDavis)Dan Portnoy (MCB)Jonathan DG Jones, Sainsbury Laboratory (UK)

Thanks to the National Science Foundation for continued support

Group Members:Wayne Christopher, Ph.D.Bob Edgar, Ph.D.Duncan BrownDan Holliman

And a number of talented undergrads:Jenny Liu, Jason Chan, Eric Roller, Joey Davis, Michael Jurka, Sonia Wu

2

Genomics / bioinformatics /computational biology

Biology Mathematics

Computer Science

Chemistry & Pharmacology

Ethics & Law

Engineering

3

Algorithm development

• Protein fold prediction and homolog identification

• Phylogenetic inference

• Structure-function analysis and prediction

– Predict structural motifs conferring functional specificity

– Effects of allelic variation on protein function/structure

• Identify structural domains

• Pathway dissection, using prediction of protein-protein

(and other inter-molecular) interactions

BioE 144: “Intro to Protein Informatics”

4

What is remote homolog detection?

1MYN

Drosomycin, Antifungal proteinFruit Fly

Antimicrobial Protein 1Common horse chestnut

1BK8

22% Pairwise identity

5

1TRY

TRYPSINFusarium Oxysporum (Fungus)

EXFOLIATIVE TOXIN AStaphylococcus aureus (Bacteria)

16% pairwise identity

Homolog recognition in the Twilight ZoneCASP2 Target T0031

6

Predicting key positions in proteins

Src homology 2 (SH2) domain

7

Panther Molecular Function Classification

of the Human Genome

8

The Universal Protein Library (UPL)

U.S. Patent No. 6,128,587

Bayesian Evolutionary Tree Estimation (BETE): U.S. Patent No. 6,128,587

9

Trees as predictive models

Subfamilies found by BETE; Tree displayed at subfamily level.

10

Berkeley Phylogenomics Group user interface

11

Hypothesis-driven vs

Hypothesis-generating approaches

12

A Tale of Two Domains

Hidden Markov models, Potassium channels,

and excursions in the Twilight Zone

13

Nck_human(adapter protein)

ZA70_human(tyrosine-protein kinase)

Common domains are found in proteins of diverse function and

structure

(PFAM domain identification shown)

14

Domain analysis of Voltage-gated K+ channels

TNF-alpha-induced protein B12 and K+ channel tetramerization domain (1T1DA)

-2

-1

0

1

2

3

4

5

1 26 51 76 101

126

151

176

201

226

251

276

301

326

351

376

401

426

451

476

501

MSA columns

log

like

liho

od

Tetramerizationdomain of K+channels

Similar to TNF-alpha-inducedprotein B12 (30seqs)

HMM positions

15

There’s a connection...There’s a connection...

16

Predictions:

Structure of TNF-alpha induced protein B12 is homologous to K+ channel tetramerization domain

TNF-alpha affects K+ current by

inducing protein B12, which

interacts with the K+ channel at tetramerization domain.

TNF-alpha-induced protein B12 and K+ channel tetramerization domain (1T1DA)

-2

-1

0

1

2

3

4

5

1 29 57 85 113

141

169

197

225

253

281

309

337

365

393

421

449

477

505

MSA columns

log

likel

iho

od

Tetramerization domain ofK+ channels

Similar toTNF-alpha-inducedprotein B12(30 seqs)

1T1DATetramerization Domain

of K+ channels

17

Investigation into innate immunity

Brian Staskawicz (Plant & Microbial Biology)Barbara Baker (Plant & Microbial Biology)

Richard Michelmore (UCDavis)Dan Portnoy (MCB)

Jonathan DG Jones, Sainsbury Laboratory (UK)

18

Plant and Animal Innate Immunity Mediated by Related Proteins

Cytoplasmic Toll Interleukin 1 Receptor (TIR) domain

19

1ICAInsect Defensin AAntibacterial proteinFlesh Fly

1MYN

Antimicrobial Protein 1 Common horse chestnut

1BK8

Drosomycin, Antifungal proteinFruit Fly

Toxin 2 Mexican scorpion(Na+ channel inhibitor)

1CN2

Defensin-related proteins

20

Gordon Research Conference on Bioinformatics24-29 Aug 2003 Oxford University

www.grc.org

21

UC Berkeley Phylogenomics

Investigation of innate immunity in plants and animals: Brian Staskawicz (Plant & Microbial Biology)Barbara Baker (Plant & Microbial Biology)Richard Michelmore (UCDavis)Dan Portnoy (MCB)Jonathan DG Jones, Sainsbury Laboratory (UK)

Thanks to the National Science Foundation kimmen@uclink.berkeley.edu http://phylogenomics.berkeley.edu

Group Members:Wayne Christopher, Ph.D.Bob Edgar, Ph.D.Duncan BrownDan Holliman

And a number of talented undergrads:Jenny Liu, Jason Chan, Eric Roller, Joey Davis, Michael Jurka, Sonia Wu