Joel L. Sussman

Intrinsically Disordered Proteins: Why are they More Abundant in Higher Organisms?

Recent studies have identified a family of neural cell single-pass transmembrane adhesion proteins, with substantial sequence similarity to cholinesterases (ChEs), i.e. cholinesterase-like adhesion molecules (CLAMs)1,2. CLAMs are devoid of catalytic activity, as they lack residues of the catalytic triad. They appear to play key roles in the earliest stages of the development of the CNS and mutations in them have been associated with autism3.

The cytoplasmic domains of CLAMs bear no sequence homology to any known protein, and physicochemical studies show that they are ‘Intrinsically Disordered Proteins (IDP)4 when expressed in E. coli1,2. It has been estimated that many cellular proteins exist in this disordered state; e.g., for mammals, about half of their total proteins are predicted to contain long disordered regions4. We developed FoldIndex© (http://bioportal.weizmann.ac.il/fldbin/findex)5, which predicts regions of a protein sequence that are likely to be disordered and have used it to examine the CLAMs family. These ‘in silico’ studies will be compared with our recent solution studies on CLAMs and their adhesion partners, as well as our studies on the life-time of IDPs in vivo6,7 FoldIndex© is also being used in the ISPC (http://www.weizmann.ac.il/ISPC) to aid in crystallization of proteins by predicting which regions of a protein sequence are likely to be disordered. Examples of IDPs will be shown in a new web tool, Proteopedia, the collaborative 3D encyclopedia of proteins & other molecules8 (http://www.proteopedia.org).

Ref:

1.  Zeev-Ben-Mordehai et al & Sussman Proteins 53, 758 (2003)
2.  Paz, et al & Silman Biophys J 95, 1928 (2008)
3.  Edelman et al & Ebstein PLoS ONE (in press) (2011)
4.  Dunker, Silman, Uversky & Sussman Curr Opin Struct Biol 18, 756 (2008)
5.  Prilusky et al & Sussman Bioinformatics 21, 3435 (2005)
6.  Tompa et al & Sussman Proteins 71, 903 (2008)
7.  Tsvetkov et al & Shaul Proteins 70, 1357 (2008)
8.  Hodis et al & Sussman Genome Biol 9, R121 (2008)

Joel L. Sussman is Professor in The Israel Structural Proteomics Center (ISPC) at the Weizmann Institute of Science.  For more information, please visit: http://www.weizmann.ac.il/ISPC