classification: understanding the diversity and principles of

MCSG 2001 structures

protein structure and function

Classification: understanding the diversity and principles of

Protein structure classification Main reference: Robert B. Russell (2002) Classification of Protein Folds. Molecular Biotechnology 20:17-28. Importance: central to studies of protein structure, function, and evolution Philosophy: phyletic vs. phenetic Method: structure comparison + human knowledge

Approaches Hierarchical Based on the types and arrangements of

secondary structures Unit (level): domain Domain assignment - structural vs. functional (fold or function

in isolation) - automated assignment methods

(structure vs. sequence)

Assignment of Class All or All (could be subjective) / ( unit) or + Other classes

Subjective class assignment

Assignment of Fold Defined by the number, type, and arrangement of SSEs Connectivity (e.g. circular permutation, scrambled proteins)

N

C

AB

DC N

CA

B

DC

..A..B..C..D.. ..C..D..A..B..

Circular Permutation (CP)

1nls (Concanavalin) 1led (Lectin)

N

C

N C

Circular permutation example

N

CN

C

1au1a_ (Interferon-) 2occc_ (Cytochrome C oxidase)

Scrambled protein pairs

Assignment of Superfamily Homologous even in the absence of

significant sequence similarity - certain level of structural similarity - unusual structural features - low but significant sequence similarity

from structural alignment - key active site residues - sequence similarity bridges Divergence vs. convergence

Assignment of Family significant sequence similarity

superfolds, superfamilies, supersites TIM barrel, Rossmann-like, ferredoxin-like, b-propellers, 4-helix bundle, Ig-like, b-jelly rolls, Oligonucleotide/oligosaccharride binding (OB) fold, SH3-like. Structure -> function (only 50% correct)

Structure implicates function?

Classification databases SCOP - careful assignment of evolutionary relationships; homologous vs. analogous CATH - A:architecture FSSP - a list of structural neighbors VAST - NCBI’s Entrez

CATH

Common Folds

Unique Folds

Structure Comparison

• Evolutionary relationship• Structure classification

Growth factorCytokine

Shapiro & Harris, 2000

9% sequence identity

Structure Comparison Tools DALI ( http://www2.ebi.ac.uk/dali/ ) CE ( http://cl.sdsc.edu/ ) VAST (http://www.ncbi.nlm.nih.gov/Structure/VAST/vast.html

) Prosup ( http://www.came.sbg.ac.at ) FLASH (http://thr.ibms.sinica.edu.tw/flash/)