Sequence Homology

Treat or Trick?

Fine Grain Structural Classification using the T-RMSD method

Cedric NotredameLuis SerranoCedrik MagisFrançois StricherAlmer van der Slot

Same sequence Same structure

SameFunctio

n

SameOrigin

Same3D fold

SameSequen

ce

Same sequence Same structure ???

100% IdenticalSequence

Prion proteinPrP-c

(normal)

>P04156|23-230 / PRIO_HUMANKKRPKPGGWNTGGSRYPGQGSPGGNRYPPQGGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQGGGTHSQWNKPSKPKTNMKHMAGAAAAGAVVGGLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYYQRGS

Prion proteinPrP-sc

(pathology)

100% IdenticalSequence

TNF Receptors (TNFRs)

Aggarwal, BB. Nat Rev Immunol. 2003 Sep;3(9):745-56.

Receptor Ligand

Intra Extra

TNFRs: The Cystein Rich Domains (CRDs)

Turn1

Loop1

Turn2

Loop2

TNFR and CRD Collections

Domain Databases

34

25 annotatednot identified

010

4

1

217

6 putatives not identified

UNIPROT

This suggests the CRDs are homogenous

Is it supported by 3D Superposition ?

Classifications

If they are so different and diverse– Can we classify them?– Can this classification bring functional information?

Structurally?

Not really…

Phylogeny?

Not quite there…

Add-hoc?

Maybe…

Add-hoc?

Maybe…Bodmer, JL., Schneider, P., Tschopp, J. Trends Biochem. Sci. 2002 Jan;27(1):19-26.

Add-hoc?

Half Domains Complex Explains Little

Maybe…

A new Classification ?

Is it possible to design a new classification– Structure based – Functionally informative– Predictive for TNFRs without a known structure

Yes if we can compare structures in a more informative way

The Standard Way: RMSD(Root Mean Square Deviation)

RMSD– Superpose the

Structures– Measure The deviation

D1 D2

D3

Y

X

W

Z

A Simpler Alternative: the iRMSD

D2

D1

D1

D2

T-RMSD: Trees based on iRMSD

d1

DistanceMatrix

P1

P1

UPGMAA

B

C

D

B

d2

ABCD

T-RMSD: Trees based on iRMSD

d1 d2

Consensus Tree

P1

A

B

C

D

C

B

A

D

A

B

C

D

C

B

A

D

ABCD

T-RMSD Vs Clustering

T-RMSD Vs Clustering

Does The Clustering Make Sense ?

Well Conserved Inserts ?

What Does the New Classification Predict ?

Type IType IIType IIIOutliers

What Does the New Classification Predict ?

Type IType IIType IIIOutliers

Nter CRDs (Pre Ligand Assembly

Domains, PLAD) are involved in the

complex formation

Next ???

New Classes ? New Functions ? New Structures

???

Next ???

Which Ligand How To Align These

things– MSA problem???

Summary

T-RMSD– Fine Grain Structural Classification

TNFRs/CRD– New typology– Structurally meaningful– Functionally informative– Predictive

T-RMSD is available for download and part of the T-Coffee package (www.tcoffee.org)

Collaborators

– Cedrik Magis– François Stricher– Almer van der Slot– Luis Serrano– Cedric Notredame