SIGBIO29

1. Structure prediction with FAMS for proteins
screened critically to autoimmune diseases
based upon bioimformatics
Shigeharu Ishida (Dept. Phys., Chuo Uinv.)
Hideaki Umeyama (Dept. Bio. Sci., Chuo Univ.)
Mitsuo Iwadate (Dept. Bio. Sci., Chuo Univ.)
Y-h. Taguchi (Dept. Phys., Chuo Uinv.)

2. 1. Introduction
Autoimmune disease:
“Autoimmune disease arise from an
inappropriate immune response of the body
against substances and tissues normally
present in the body.”
Ex.
Rheumatoid Arthritis (RA; 関節リウマチ）
Alopecia areata （円形脱毛症）

3. ２． Previous findings …
B. M. Javierre et al (2010)
Genome Res. 20[2] pp 170-179
Target:
Systemic lupus erythematosus
(SLE;全身性エリテマトーデス )
RA
Dermatomyositis (DM;皮膚筋炎 )
Seek common promoter methylation
→ SLE Only

4. Y-h. Taguchi, DMSM2010 (2010)
http://www.ai-gakkai.or.jp/jsai/sig/dmsm/012/
Successfully picked up 33 promoters commonly
methylated for RA, SLE, and DM.
But, no biological validations …..
Data base : ☓ , Blast : ☓
In this paper, we show that protein structure
prediction by FAMS is useful tool for functional
annotation of proteins and also possibly useful
for drug discovery...

5. 3. FAMS (Full Automatic Modeling System)
“The computer program FAMS performs
homology modeling of protein structures by
means of an algorithm consisting of database
searches and simulated annealing.”
Umeyama & Iwadate (2004)
Curr Protoc Bioinformatics.

6. 4. Results
Reference Model
genesymbol PDBID P-value gene symbol
AIM2 2OQ0_B 4.00E-92 GAMMA-INTERFERON-INDUCIBLE PROTEIN IFI-16
CARD15 3CIY_B 7.00E-64 TOLL-LIKE RECEPTOR 4, VARIABLE LYMPHOCYTE (TLR4)
CD82 2BG9_A 4.60E-01 ACETYLCHOLINE RECEPTOR PROTEIN, ALPHA CHAIN
CSF1R 3B43_A 5.00E-83 TITIN
CSF3 1GNC_A 2.00E-66 GRANULOCYTE COLONY-STIMULATING FACTOR
CSF3R 3DMK_A 1.00E-71 DOWN SYNDROME CELL ADHESION MOLECULE (DSCAM)
DHCR24 2Q4W_A 1.00E-115 CYTOKININ DEHYDROGENASE 7 (CKO7)
ERCC3 2W74_D 1.00E-152 TYPE I RESTRICTION ENZYME ECOR124IIR PROTEIN (HSDR)
GRB7 3HK0_B 2.00E-73 GROWTH FACTOR RECEPTOR-BOUNDP ROTEIN10 (GRB10)
HGF 2F83_A 1.00E-111 COAGULATION FACTOR XI
HOXB2 2D5V_A 9.00E-24 HEPATOCYTE NUCLEAR FACTOR 6 (HNF-6)
IFNGR2 1FNF_A 1.00E-37 FIBRONECTIN
LCN2 1X71_A 1.00E-51 NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL)
LMO2 2XJY_A 2.00E-33 RHOMBOTIN-2
LTB4R 2KS9_A 2.00E-83 SUBSTANCE-P RECEPTOR
MMP14 1SU3_B 1.00E-160 INTERSTITIAL COLLAGENASE (MMP-1)
MMP8 1SU3_B 1.00E-171 INTERSTITIAL COLLAGENASE (MMP-1)
MPL 3L5H_A 4.00E-63 INTERLEUKIN-6 RECEPTOR SUBUNIT BETA (IL6RB)
PAD14 2DEW_ X 0.00E+00 PROTEIN-ARGININE DEIMINASE TYPE IV
PECAM1 3DMK_A 1.00E-104 DOWN SYNDROME CELL ADHESION MOLECULE (DSCAM)
PI3 1TWP_A 2.00E-19 WHEY ACIDIC PROTEIN (WAP)
RARA 3DZY_A 4.00E-95 RETINOIC ACID RECEPTOR RXR-ALPHA
S100A2 2RGI_A 4.00E-19 PROTEIN S100-A2
SEPT9 3FTQ_A 1.00E-137 SEPTIN-2
SLC22A18 1PW4_A 1.00E-108 GLYCEROL-3-PHOSPHATE TRANSPORTER
SPI1 1GVJ_B 1.00E-21 C-ETS-1 PROTEIN (ETS1)
SPP1 1D2T_A 3.00E-14 ACID PHOSPHATASE (ACP)
STAT5A 1Y1U_ A 0.00E+00 SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT5A
SYK 2OZO_A 1.00E-168 TYROSINE-PROTEIN KINASE ZAP-70
TIE1 3DMK_A 2.00E-84 DOWN SYNDROME CELL ADHESION MOLECULE (DSCAM)
TM7SF3 [1AR1_A] 6.00E-88 CYTOCHROME C OXIDASE
TRIP6 1B8T_A 2.00E-32 CYSTEINE-RICH PROTEIN1 (CRP1)
VAMP8 2KOG_A 1.00E-21 VESICLE-ASSOCIATED MEMBRANE PROTEIN 2 (VAMP2)

7. ・Almost all proteins are modeled with very
small P-values (〜10E-20) (with high
significance)
・Obtained proteins have functional annotations
(because they are listed in PDB)
⇒ Protein structure prediction by FAMS turns
out to be also useful for functional annotation,
because model protein registered in PDB is often
well studied and annotated. (Otherwise none
hope to decide 3D structure with much effort and
money!)

8. ・Almost all functional annotations are
related to immunology/autoimmune
⇓
３３ selected promoters turned out to be
biologically meaningful
e.g., AIM2 modeled by IFI-16
“Structures of the HIN Domain: DNA
Complexes Reveal Ligand Binding and
Activation Mechanisms of the AIM2
Inflammasome and IFI16 Receptor”
Jin et al (2012/4/20) Immunity.

9. 5. To Drug Discovery...
5.1 Ligand Search
mmp8/14 are modeled by mmp1. Ligand designed
for mmp1 possibly can bind to mmp8/14, too.
mmp8 mmp14

10. 5.2 Search for protein complex
Protein A Protein Complex Protein B
in PDB
Protein Complex Candidate

11. Huge number of protein complex candidates were
found....
CSF1R
PECAM1 410

12. CSF1R vs PECAM1 modeled by 2ZJS

13. Why protein complex?
If we can terminate protein complex
formation by finding molecules to bind
interface between two proteins, they can be
drug.

14. 6. Conclusion
・FAMS predicts protein structure of genes
whose promoter are commonly de/methylated
for autoimmune.
・Protein structure prediction is useful for
functional annotation
・It also helps ligand search
・ FAMS is also useful protein complex
inference which may lead to drug discovery